Pyrrole compounds that modulate HSP90 activity

ABSTRACT

The present invention relates to substituted pyrrole compounds and compositions comprising substituted pyrrole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a substituted pyrrole compound of the invention, or a pharmaceutical composition comprising such a compound.

RELATED APPLICATION

This application is a divisional application of U.S. application Ser.No. 13/902,290, filed May 24, 2013, which is a divisional of U.S.application Ser. No. 12/995,714, filed Feb. 18, 2011 which is a U.S.National Stage of International Application No. PCT/US2009/003390, filedJun. 4, 2009, which claims the priority benefit of U.S. Provisionalapplication No. 61/130,921, filed Jun. 4, 2008. The entire teachings ofthe above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Although tremendous advances have been made in elucidating the genomicabnormalities that cause malignant cancer cells, currently availablechemotherapy remains unsatisfactory, and the prognosis for the majorityof patients diagnosed with cancer remains dismal. Most chemotherapeuticagents act on a specific molecular target thought to be involved in thedevelopment of the malignant phenotype. However, a complex network ofsignaling pathways regulate cell proliferation and the majority ofmalignant cancers are facilitated by multiple genetic abnormalities inthese pathways. Therefore, it is unlikely that a therapeutic agent thatacts on one molecular target will be fully effective in curing a patientwho has cancer.

Heat shock proteins (HSPs) are a class of chaperone proteins that areup-regulated in response to elevated temperature and other environmentalstresses, such as ultraviolet light, nutrient deprivation and oxygendeprivation. HSPs act as chaperones to other cellular proteins (calledclient proteins), facilitate their proper folding and repair and aid inthe refolding of misfolded client proteins. There are several knownfamilies of HSPs, each having its own set of client proteins. The Hsp90family is one of the most abundant HSP families accounting for about1-2% of proteins in a cell that is not under stress and increasing toabout 4-6% in a cell under stress. Inhibition of Hsp90 results in thedegradation of its client proteins via the ubiquitin proteasome pathway.Unlike other chaperone proteins, the client proteins of Hsp90 are mostlyprotein kinases or transcription factors involved in signaltransduction, and a number of its client proteins have been shown to beinvolved in the progression of cancer. Examples of Hsp90 client proteinsthat have been implicated in the progression of cancer are describedbelow.

Her2 is a transmembrane tyrosine kinase cell surface growth factorreceptor that is expressed in normal epithelial cells. Her2 has anextracellular domain that interacts with extracellular growth factorsand an internal tyrosine kinase portion that transmits the externalgrowth signal to the nucleus of the cell. Her2 is overexpressed in asignificant proportion of malignancies, such as breast cancer, ovariancancer, prostate cancer and gastric cancers, and is typically associatedwith a poor prognosis.

Akt kinase is a serine/threonine kinase which is a downstream effectormolecule of phosphoinositide 3-kinase and is involved in protecting acell from apoptosis. Akt kinase is thought to be involved in theprogression of cancer because it stimulates cell proliferation andsuppresses apoptosis.

Cdk4/cyclin D complexes are involved in phosphorylation of theretinoblastoma protein, which is an essential step in progression of acell through the G1 phase of the cell cycle. Disruption of Hsp90activity has been shown to decrease the half life of newly synthesizedCdk4.

Raf-1 is a MAP 3-kinase (MAP3K) which, when activated, can phosphorylateand activate the serine/threonine specific protein kinases ERK1 andERK2. Activated ERKs play an important role in the control of geneexpression involved in the cell division cycle, apoptosis, celldifferentiation and cell migration.

The transforming protein of the Rous sarcoma virus, v-src, is aprototype of an oncogene family that induces cellular transformation(i.e., tumorogenesis) by non-regulated kinase activity. Hsp90 has beenshown to complex with v-scr and inhibit its degradation.

Hsp90 is required to maintain steroid hormone receptors in conformationscapable of binding hormones with high affinity. Inhibition of the actionof Hsp90 therefore is expected to be useful in treatinghormone-associated malignancies such as breast cancer.

p53 is a tumor suppressor protein that causes cell cycle arrest andapoptosis. Mutation of the p53 gene is found in about half of all humancancers, making it one of the most common genetic alterations found incancerous cells. In addition, the p53 mutation is associated with a poorprognosis. Wild-type p53 has been shown to interact with Hsp90, butmutated p53 forms a more stable association with Hsp90 than wild-typep53 as a result of its misfolded conformation. A stronger interactionwith Hsp90 protects the mutated protein from normal proteolyticdegradation and prolongs its half-life. In a cell that is heterozygousfor mutated and wild-type p53, inhibition of the stabilizing effect ofHsp90 causes mutant p53 to be degraded and restores the normaltranscriptional activity of wild-type p53.

Hif-1α is a hypoxia-inducible transcription factor that is up-regulatedunder low oxygen conditions. Under normal oxygen conditions, Hif-1αassociates with the Von Hippel-Lindau (VHL) tumor suppressor protein andis degraded. Low oxygen conditions inhibit this association and allowsHif-1α to accumulate and complex with Hif-1β to form an activetranscription complex. The activated complex associates withhypoxia-response elements to trigger the transcription of vascularendothelial growth factor (VEGF). Increased Hif-1α is associated withincreased metastasis and a poor prognosis.

There are two classes of protein kinases (PKs): protein tyrosine kinases(PTKs), which catalyze the phosphorylation of tyrosine kinase residues,and the serine-threonine kinases (STKs), which catalyze thephosphorylation of serine or threonine residues. Growth factor receptorswith PTK activity are known as receptor tyrosine kinases. Receptortyrosine kinases are a family of tightly regulated enzymes, and theaberrant activation of various members of the family is one of thehallmarks of cancer. The receptor tyrosine kinase family can be dividedinto subgroups that have similar structural organization and sequencesimilarity within the kinase domain.

Epidermal Growth Factor Receptor (EGFR) is a member of the type 1subgroup of receptor tyrosine kinase family of growth factor receptorswhich play critical roles in cellular growth, differentiation andsurvival. Activation of these receptors typically occurs via specificligand binding which results in hetero- or homodimerization betweenreceptor family members, with subsequent autophosphorylation of thetyrosine kinase domain. Specific ligands which bind to EGFR includeepidermal growth factor (EGF), transforming growth factor α (TGFα),amphiregulin and some viral growth factors. Activation of EGFR triggersa cascade of intracellular signaling pathways involved in both cellularproliferation (the ras/raf/MAP kinase pathway) and survival (the PI3kinase/Akt pathway). Members of this family, including EGFR and HER2,have been directly implicated in cellular transformation.

A number of human malignancies are associated with aberrant oroverexpression of EGFR and/or overexpression of its specific ligands.Gullick, Br. Med. Bull. (1991), 47:87-98; Modijtahedi & Dean, Int. J.Oncol. (1994), 4:277-96; Salomon, et al., Crit. Rev. Oncol. Hematol.(1995), 19:183-232. Aberrant or overexpression of EGFR has beenassociated with an adverse prognosis in a number of human cancers,including head and neck, breast, colon, prostate, lung (e.g., NSCLC,adenocarcinoma and squamous lung cancer), ovarian, gastrointestinalcancers (gastric, colon, pancreatic), renal cell cancer, bladder cancer,glioma, gynecological carcinomas and prostate cancer. In some instances,overexpression of tumor EGFR has been correlated with bothchemoresistance and a poor prognosis. Lei, et al., Anti-cancer Res.(1999), 19:221-28; Veale, et al., Br. J. Cancer (1993); 68:162-65.

Gefitinib, a chemotherapeutic agent that inhibits the activity of EGFR,has been found to be highly efficacious in a subset of lung cancerpatients that have mutations in the tyrosine kinase domain of EGFR. Inthe presence of EGF, these mutants displayed two to three times higheractivity than wild type EGFR. In addition, wild type EGFR wasinternalized by the cells and down-regulated after 15 minutes, whereasmutant EGFR was internalized more slowly and continued to be activatedfor up to three hours. Lynch, et al., New Eng. J. Med. (2006),350:2129-2139.

Gliomas are another type of cancer that is characterized by theamplification and/or mutation of the EGFR gene. One of the most commonmutations in the EGFR gene is a deletion of exons 2-7 which results in atruncated form of EGFR in which amino acids 6-273 of the extracellulardomain are replaced with a single glycine residue. This mutation iscalled EGFRvIII and is expressed in about half of all glioblastomas.EGFRvIII is unable to bind EGF and TGFα and has constitutive,ligand-independent tyrosine kinase activity. Hsp90 co-purifies withEGFRvIII, indicating that Hsp90 complexes with EGFRvIII. Moreover, theHsp90 inhibitor geldanamycin, a benzoquinone ansamycin antibiotic, isable to decrease the expression of EGFRvIII, indicating that interactionwith Hsp90 is essential to maintain high expression levels of EGFRvIII.Lavictoire, et al., J. Biological Chem. (2003), 278(7):5292-5299. Theseresults demonstrate that inhibiting the activity of Hsp90 is aneffective strategy for treating cancers that are associated withinappropriate EGFR activity.

The members of the type III group of receptor tyrosine kinases includeplatelet-derived growth factor receptors (PDGF receptors alpha andbeta), colony-stimulating factor receptor (CSF-1R, c-Fms), Fms-liketyrosine kinase (FLT3), and stem cell factor receptor (c-Kit). FLT3 isprimarily expressed on immature hematopoietic progenitors and regulatestheir proliferation and survival.

Hematologic cancers, also known as hematologic or hematopoieticmalignancies, are cancers of the blood or bone marrow, includingleukemia and lymphoma. Acute myelogenous leukemia (AML) is a clonalhematopoietic stem cell leukemia that represents about 90% of all acuteleukemias in adults with an incidence of 3.9 per 100,000. See e.g.,Lowenberg, et al., N. Eng. J. Med. (1999), 341: 1051-62; Menezes, etal., Clin. Cancer Res. (2005), 11(14):5281-5291. While chemotherapy canresult in complete remissions, the long term disease-free survival ratefor AML is about 14%, with about 7,400 deaths from AML each year in theUnited States. Approximately 70% of AML blasts express wild type FLT3and about 25% to about 35% express FLT3 kinase receptor mutations whichresult in constitutively active FLT3. Two types of activating mutationshave been identified in AML patients: internal tandem duplications(ITDs) and point mutation in the activating loop of the kinase domain.FLT3-ITD mutations in AML patients are indicative of a poor prognosisfor survival. In patients who are in remission, FLT3-ITD mutations arethe most significant factor adversely affecting relapse rate with 64% ofpatients having the mutation relapsing within 5 years. See Advani,Current Pharmaceutical Design (2005), 11:3449-3457. The prognosticsignificance of FLT3 mutations in clinical studies suggests that FLT3plays a driving role in AML and may be necessary for the development andmaintenance of the disease.

Mixed Lineage Leukemia (MLL) involves translocations of chromosome 11band q23 (11q23) and occurs in approximately 80% of infant hematologicalmalignancies and 10% of adult acute leukemias. Although certain 11q23translocations have been shown to be essential to immortalization ofhematopoietic progenitors in vitro, a secondary genotoxic event isrequired to develop leukemia. There is a strong concordance between FLT3and MLL fusion gene expression, and the most consistently overexpressedgene in MLL is FLT3. Moreover, it has been shown that activated FLT3together with MLL fusion gene expression induces acute leukemia with ashort latency period. See Ono, et al., J. Clinical Investigation (2005),115:919-929. Therefore, it is believed that FLT3 signaling is involvedin the development and maintenance of MLL. Armstrong, et al., CancerCell (2003), 3:173-183.

The FLT3-ITD mutation is also present in about 3% of cases of adultmyelodysplastic syndrome and some cases of acute lymphocytic leukemia(ALL). Advani, Current Pharmaceutical Design (2005), 11:3449-3457.

FLT3 has been shown to be a client protein of Hsp90, and 17AAG, abenzoquinone ansamycin antibiotic that inhibits Hsp90 activity, has beenshown to disrupt the association of FLT3 with Hsp90. The growth ofleukemia cells that express either wild type FLT3 or FLT3-ITD mutationswas found to be inhibited by treatment with 17AAG. Yao, et al., ClinicalCancer Research (2003), 9:4483-4493.

c-Kit is a membrane type III receptor protein tyrosine kinase whichbinds Stem Cell Factor (SCF) to its extracellular domain. c-Kit hastyrosine kinase activity and is required for normal hematopoiesis.However, mutations in c-Kit can result in ligand-independent tyrosinekinase activity, autophosphorylation and uncontrolled cellproliferation. Aberrant expression and/or activation of c-Kit has beenimplicated in a variety of pathologic states. For example, there isevidence of a contribution of c-Kit to neoplastic pathology, includingits association with leukemias and mast cell tumors, small cell lungcancer, testicular cancer and some cancers of the gastrointestinal tractand central nervous system. In addition, c-Kit has been implicated incarcinogenesis of the female genital tract, sarcomas of neuroectodermalorigin, and Schwann cell neoplasia associated with neurofibromatosis.Yang et al., J Clin Invest. (2003), 112:1851-1861; Viskochil, J ClinInvest. (2003), 112:1791-1793. c-Kit has been shown to be a clientprotein of Hsp90, and Hsp90 inhibitor 17AAG has been shown to induceapoptosis in Kasumi-1 cells, an acute myeloid leukemia cell line thatharbors a mutation in c-Kit.

c-Met is a receptor tyrosine kinase that is encoded by the Metprotooncogene and transduces the biological effects of hepatocyte growthfactor (HGF), which is also referred to as scatter factor (SF). Jiang,et al., Crit. Rev. Oncol. Hemtol. (1999), 29: 209-248. c-Met and HGF areexpressed in numerous tissues, although their expression is normallypredominantly confined to cells of epithelial and mesenchymal origin,respectively. c-Met and HGF are required for normal mammaliandevelopment and have been shown to be important in cell migration, cellproliferation, cell survival, morphogenic differentiation and theorganization of 3-dimensional tubular structures (e.g., renal tubularcells, gland formation, etc.). The c-Met receptor has been shown to beexpressed in a number of human cancers. c-Met and its ligand, HGF, havealso been shown to be co-expressed at elevated levels in a variety ofhuman cancers, particularly sarcomas. However, because the receptor andligand are usually expressed by different cell types, c-Met signaling ismost commonly regulated by tumor-stroma (tumor-host) interactions.Furthermore, c-Met gene amplification, mutation and rearrangement havebeen observed in a subset of human cancers. Families with germinemutations that activate c-Met kinase are prone to multiple kidneytumors, as well as tumors in other tissues. Numerous studies havecorrelated the expression of c-Met and/or HGF/SF with the state ofdisease progression of different types of cancer, including lung, colon,breast, prostate, liver, pancreas, brain, kidney, ovarian, stomach, skinand bone cancers. Furthermore, the overexpression of c-Met or HGF havebeen shown to correlate with poor prognosis and disease outcome in anumber of major human cancers including lung, liver, gastric and breast.

BCR-ABL is an oncoprotein with tyrosine kinase activity that has beenassociated with chronic myelogenous leukemia (CML), acute lymphocyticleukemia (ALL) in a subset of patients and acute myelogenous leukemia(AML) in a subset of patients. In fact, the BCR-ABL oncogene has beenfound in at least 90-95% of patients with CML, about 20% of adults withALL, about 5% of children with ALL and in about 2% of adults with AML.The BCR-ABL oncoprotein is generated by the transloction of genesequences from the c-ABL protein tyrosine kinase on chromosome 9 intothe BCR sequences on chromosome 22, producing the Philadelphiachromosome. The BCR-ABL gene has been shown to produce at least threealternative chimeric proteins, p230 BCR-ABL, p210 BCR-ABL and p190BCR-ABL, which have unregulated tyrosine kinase activity. The p210BCR-ABL fusion protein is most often associated with CML, while the p190BCR-ABL fusion protein is most often associated with ALL. BCR-ABL hasalso been associated with a variety of additional hematologicalmalignancies including granulocytic hyperplasia, myelomonocyticleukemia, lymphomas and erythroid leukemia.

Studies have shown that lowering the expression or activity of BCR-ABLis effective in treating BCR-ABL-positive leukemias. For example, agentssuch as As₂O₃ which lower BCR-ABL expression have been shown to behighly effective against BCR-ABL leukemias. In addition, inhibition ofBCR-ABL tyrosine kinase activity by Imatinib (also known as STI571 andGLEEVEC) induces differentiation and apoptosis and causes eradication ofBCR-ABL positive leukemia cells both in vivo and in vitro. In patientswith CML in the chronic phase, as well as in a blast crisis, treatmentwith Imatinib typically will induce remission. However, in many cases,particularly in those patients who were in a blast crisis beforeremission, the remission is not durable because the BCR-ABL fusionprotein develops mutations that cause it to be resistance to Imatinib.Nimmanapalli, et al., Cancer Research (2001), 61:1799-1804; Gorre, etal., Blood (2002), 100:3041-3044.

BCR-ABL fusion proteins exist as complexes with Hsp90 and are rapidlydegraded when the action of Hsp90 is inhibited. It has been shown thatgeldanamycin, a benzoquinone ansamycin antibiotic that disrupts theassociation of BCR-ABL with Hsp90, results in proteasomal degradation ofBCR-ABL and induces apoptosis in BCR-ABL leukemia cells.

Hsp90 has been shown by mutational analysis to be necessary for thesurvival of normal eukaryotic cells. However, Hsp90 is over expressed inmany tumor types indicating that it may play a significant role in thesurvival of cancer cells, and that cancer cells may be more sensitive toinhibition of Hsp90 than normal cells. For example, cancer cellstypically have a large number of mutated and overexpressed oncoproteinsthat are dependent on Hsp90 for folding. In addition, because theenvironment of a tumor is typically hostile due to hypoxia, nutrientdeprivation, acidosis, etc., tumor cells may be especially dependent onHsp90 for survival. Moreover, inhibition of Hsp90 causes thesimultaneous inhibition of a number of oncoproteins, hormone receptorsand transcription factors, thus making it an attractive target for ananti-cancer agent. In fact, benzoquinone ansamycins, a family of naturalproducts that inhibit Hsp90, have shown evidence of therapeutic activityin clinical trials.

Although promising, benzoquinone ansamycins, and their derivatives,suffer from a number of limitations. For example, they have low oralbioavailability and their limited solubility makes them difficult toformulate. In addition, they are metabolized by polymorphic cytochromeP450 CYP3A4 and are a substrate for the P-glycoprotein export pumpinvolved in the development of multidrug resistance. Therefore, a needexists for new therapeutics that improve the prognosis of cancerpatients and that reduce or overcome the limitations of currently usedanti-cancer agents.

HSPs are highly conserved from microorganisms to mammals. When apathogen invades a host, both the pathogen and the host increase HSPproduction. HSPs appear to play various roles in the infection process.For instance, Hsp90 has been shown to play a role in the pathwaysinvolved in the uptake and/or killing of bacteria in phagocytic cells.Yan, L., et al., Eukaryotic Cell (2004), 3(3):567-578. Hsp90 has alsobeen shown to be essential for the uptake of binary actinADP-ribosylating toxins into eukaryotic cells. Haug, G., Infection andImmunity (2004), 12:3066-3068. Additionally, Hsp90 has been identifiedas playing a role in viral proliferation in a number of virusesincluding influenza virus, vaccinia virus, herpes simplex virus type Iand HIV-1 virus. Momose, F., et al., J. Biol. Chem. (2002),277(47):45306-45314; Hung, J., et al., J. Virology (2002),76(3)1379-1390; Li, Y., et al., Antimicrobial Agents and Chemotherapy(2004), 48(3):867-872; O'Keefe, B., et al., J. Biol. Chem. (2000),275(1):279-287.

Opportunistic fungal infections that are resistant to antifungal drugshave become an increasing problem, particularly in immunocompromisedpatients. Hsp90 has been shown to play a role in the evolution of drugresistance in fungi. Cowen, L., et al., Eukaryotic Cell (2006),5(12):2184-2188; Cowen, L., et al., Science (2005), 309:2185-2189.

SUMMARY OF THE INVENTION

The invention provides in one aspect, HSP90 inhibitors according toFormula (I). These compounds are suitable for the treatment ofhyperproliferative diseases such as cancer, infections, immune disordersand inflammation.

It is furthermore an aspect of the present invention to provide an HSP90inhibitor according to

Formula (I) for use as a medicament. Another aspect of the presentinvention provides an HSP90 inhibitor according to Formula (I) for thepreparation of a medicament for the treatment of a hyperproliferativedisease, such as cancer or inflammation. The present invention alsoprovides the use of a compound according to Formula (I) for treating asubject with a hyperproliferative disease such as cancer, infection,immune disorder and inflammation.

In one embodiment, the present invention provides compounds representedby structural formula (I):

or a pharmaceutically acceptable salt thereof.

Wherein each R¹ and R² is independently —NR¹⁰R¹¹, —OR⁷, —SR⁷,—OC(O)NR¹⁰R¹¹, —SC(O)NR¹⁰R¹¹, —NR²C(O)NR¹⁰R¹¹, —OC(O)R⁷, —SC(O)R⁷,—NR⁷C(O)R⁷, —OC(O)OR⁷, —SC(O)OR⁷, —NR⁷C(O)OR⁷, —OCH₂C(O)R⁷, —SCH₂C(O)R⁷,—NR⁷CH₂C(O)R⁷, —OCH₂C(O)OR⁷, —SCH₂C(O)OR⁷, —NR⁷CH₂C(O)OR⁷,—OCH₂C(O)NR¹⁰R¹¹, —SCH₂C(O)NR¹⁰R¹¹, —NR⁷CH₂C(O)NR¹⁰R¹¹, —OS(O)_(p)R⁷,—SS(O)_(p)R⁷, —S(O)_(p)OR⁷, —NR⁷S(O)_(p)R⁷, —OS(O)_(p)NR¹⁰R¹¹,—SS(O)_(p)NR¹⁰R¹¹, —NR⁷S(O)_(p)NR¹⁰R¹¹, —OS(O)_(p)OR⁷, —SS(O)_(p)OR⁷,—NR⁷S(O)_(p)OR⁷, —OC(S)R⁷, —SC(S)R⁷, —NR⁷C(S)R⁷, —OC(S)OR⁷, —SC(S)OR⁷,—NR⁷C(S)OR⁷, —OC(S)NR¹⁰R¹¹, —SC(S)NR¹⁰R¹¹, —NR⁷C(S)NR¹⁰R¹¹, —OC(NR⁷)R⁷,—SC(NR⁷)R⁷, —NR⁷C(NR⁷)R⁷, —OC(NR⁷)OR⁷, —SC(NR⁷)OR⁷, —NR⁷C(NR⁷)OR⁷,—OC(NR⁷)NR¹⁰R¹¹, —SC(NR⁷)NR¹⁰R¹¹, —NR⁷C(NR⁷)NR¹⁰R¹¹, —OP(O)(OR⁷)₂, or—SP(O)(OR⁷)₂.

R³ is hydrogen, —X⁵⁰R⁵⁰, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl,wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented byR³ is optionally and independently substituted.

Each R⁴ and R⁵ is independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, orheteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkylrepresented by R⁴ or R⁵ is optionally and independently substituted; orR⁴ and R⁵, taken together with the nitrogen to which they are attached,form an optionally substituted heterocyclyl or an optionally substitutedheteroaryl.

Each R⁷ is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl,wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented byR⁷ is optionally and independently substituted.

Each R¹⁰ and R¹¹ is independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, orheteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkylrepresented by R¹⁰ or R¹¹ is optionally and independently substituted;or R¹⁰ and R¹¹, taken together with the nitrogen to which they areattached, form an optionally substituted heterocyclyl or an optionallysubstituted heteroaryl.

Each Z is independently alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl,halo, cyano, nitro, guanadino, alkoxy, —NR¹⁰R¹¹, —OR⁷, —C(O)R⁷,—C(O)OR⁷, —C(S)R⁷, —C(O)SR⁷, —C(S)SR⁷, —C(S)OR⁷, —C(S)NR¹⁰R¹¹,—C(NR⁷)OR⁷, —C(NR⁷)R⁷, —C(NR⁷)NR¹⁰R¹¹, —C(NR⁷)SR⁷, —OC(O)R⁷, —OC(O)OR⁷,—OC(S)OR⁷, —OC(NR⁷)OR⁷, —SC(O)R⁷, —SC(O)OR⁷, —SC(NR⁷)OR⁷, —OC(S)R⁷,—SC(S)R⁷, —SC(S)OR⁷, —OC(O)NR¹⁰R¹¹, —OC(S)NR¹⁰R¹¹, —OC(NR⁷)NR¹⁰R¹¹,—SC(O)NR¹⁰R¹¹, —SC(NR⁷)NR¹⁰R¹¹, —SC(S)NR¹⁰R¹¹, —OC(NR⁷)R⁷, —SC(NR⁷)R⁷,—C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷, —NR⁷C(S)R⁷, —NR⁷C(S)OR⁷, —NR⁷C(NR⁷)R⁷,—NR⁷C(O)OR⁷, —NR⁷C(NR⁷)OR⁷, —NR⁷C(O)NR¹⁰R¹¹, —NR⁷C(S)NR¹⁰R¹¹,—NR⁷C(NR⁷)NR¹⁰R¹¹, —S(O)_(p)R⁷, —OS(O)_(p)R⁷, —OS(O)_(p)OR⁷,—OS(O)_(p)NR¹⁰R¹¹, —S(O)_(p)OR⁷, —NR⁷S(O)_(p)R⁷, —NR⁷S(O)_(p)NR¹⁰R¹¹,—NR⁷S(O)_(p)OR⁷, —S(O)_(p)NR¹⁰R¹¹, —SS(O)_(p)R⁷, —SS(O)_(p)OR⁷,—SS(O)_(p)NR¹⁰R¹¹, —OP(O)(OR⁷)₂, or —SP(O)(OR⁷)₂, wherein the alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, heteroaralkyl represented by Z are optionally andindependently substituted;

R⁵⁰ is an optionally substituted aryl or an optionally substitutedheteroaryl; X⁵⁰ is a divalent group selected from a C₁-C₄ alkylene, NR⁷,C(O), C(S), C(NR⁷), and S(O)_(p); Y is O or S; each p is independently0, 1 or 2; and n is 0, 1, 2, or 3.

The present invention provides a method of inhibiting HSP90 in a cell,comprising administering to the cell an effective amount of a compoundof Formula (I). The invention also provides a method of treating aproliferative disorder in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound ofFormula (I). Additionally, the invention provides a method of treatingcancer in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of Formula (I).

The present invention provides a method of inducing degredation of c-Kitproteins in a cell, comprising administering to the cell an effectiveamount of a compound of Formula (I). The invention encompasses a methodof treating a c-Kit associated cancer in a subject in need thereof,comprising administering to the subject an effective amount of acompound of Formula (I).

The present invention provides a method of inducing degredation ofBCR-ABL proteins in a cell, comprising administering to the cell aneffective amount of a compound of Formula (I). The invention encompassesa method of treating a BCR-ABL associated cancer in a subject in needthereof, comprising administering to the subject an effective amount ofa compound of Formula (I).

The present invention provides a method of inducing degredation of FLT3proteins in a cell, comprising administering to the cell an effectiveamount of a compound of Formula (I). The invention encompasses a methodof treating a FLT3 associated cancer in a subject in need thereof,comprising administering to the subject an effective amount of acompound of Formula (I).

The present invention provides a method of inducing degredation of EGFRproteins in a cell, comprising administering to the cell an effectiveamount of a compound of Formula (I). The invention encompasses a methodof treating a EGFR associated cancer in a subject in need thereof,comprising administering to the subject an effective amount of acompound of Formula (I).

The present invention also provides a method of treating an infection ina subject in need thereof, comprising administering to the subject aneffective amount of a compound of Formula (I). The present inventionincludes a method of treating a fungal infection in a subject in needthereof, comprising administering to the subject an effective amount ofa compound of Formula (I). The present invention includes a method oftreating a viral infection in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound ofFormula (I). The present invention includes a method of treating abacterial infection in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound ofFormula (I). The present invention includes a method of treating aparasitic infection in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound ofFormula (I).

The present invention also provides a method of inhibiting angiogenesisin a subject in need thereof, comprising administering to the subject aneffective amount of a compound of Formula (I). The invention alsoincludes a method of occluding, blocking, or otherwise disrupting theblood flow in neovasculature, comprising contacting the neovasculaturewith an effective amount of a compound of Formula (I).

The present invention provides a method for treating a non-Hodgkin'slymphoma in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of Formula (I). The inventionincludes a method of treating B-cell and/or T-cell non-Hodgkin'slymphoma.

The present invention also provides method of inhibiting the activity oftopoisomerase II in a cell, comprising administering to a cell aneffective amount of a compound of Formula (I).

The present invention also provides method of modulating the activity ofglucocorticoid receptors in a cell, comprising administering to a cellan effective amount of a compound of Formula (I).

The present invention additionally includes a method of treating aninflammatory disorder in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound ofFormula (I).

The present invention additionally includes a method of treating animmune disorder in a subject in need thereof, comprising administeringto the subject an effective amount of a compound of Formula (I). Theinvention provides a method of suppressing the immune system of asubject in need thereof, comprising administering to the subject aneffective amount of a compound of Formula (I).

The present invention further provides a pharmaceutical composition of acompound of Formula (I), comprising said compound and a pharmaceuticallyacceptable carrier. An additional embodiment of the invention includes apharmaceutical composition comprising a compound of Formula (I) and anadditional therapeutic agent.

The compounds shown in Table 1 or compounds of any formula herein, orpharmaceutically acceptable salts thereof, inhibit the activity of Hsp90and, thereby facilitates the degradation of Hsp90 client proteins. Hsp90is necessary for the survival of normal eukaryotic cells. However, Hsp90is over expressed in many tumor types indicating that it may play asignificant role in the survival of cancer cells and that cancer cellsmay be more sensitive to inhibition of Hsp90 than normal cells. Thus,the compounds shown in Table 1 or compounds of any formula herein, orpharmaceutically acceptable salts thereof, are useful treatingproliferative disorders such as cancer.

Although traditional chemotherapeutic agents may initially cause tumorregression, most agents that are currently used to treat cancer targetonly one pathway to tumor progression. Therefore, in many instances,after treatment with one or more chemotherapeutic agents, a tumordevelops multidrug resistance and no longer responses positively totreatment. One of the advantages of inhibiting Hsp90 activity is thatseveral of its client proteins, which are mostly protein kinases ortranscription factors involved in signal transduction, have been shownto be involved in the progression of cancer. Thus, inhibition of Hsp90provides a method of simultaneously short circuiting multiple pathwaysfor tumor progression. Therefore, treatment of tumors with an Hsp90inhibitor of the invention either alone, or in combination with otherchemotherapeutic agents, is more likely to result in regression orelimination of the tumor, and less likely to result in the developmentof more aggressive multidrug resistant tumors than other currentlyavailable therapies.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides, in a first aspect, novel compounds according toFormula (I) that inhibit HSP90, as well as the pharmaceuticallyacceptable salts thereof, that are useful for the treatment ofhyperproliferative disorders such as cancer, infections, immunedisorders and inflammation.

In another aspect, the invention provides compounds of Formulae (II),(III) and (IV):

Wherein the values and particular values for the variables are asdescribed for Formula (I).

In specific aspects of the invention the variables of Formulae (I)-(IV),where present, have the following meanings:

Each R¹ and R² in Formulae (I)-(IV) is independently —NR¹⁰R¹¹, —OR⁷,—SR⁷, —OC(O)NR¹⁰R¹¹, —SC(O)NR¹⁰R¹¹, —NR⁷C(O)NR¹⁰R¹¹, —OC(O)R⁷, —SC(O)R⁷,—NR⁷C(O)R⁷, —OC(O)OR⁷, —SC(O)OR⁷, —NR⁷C(O)OR⁷, —OCH₂C(O)R⁷, —SCH₂C(O)R⁷,—NR⁷CH₂C(O)R⁷, —OCH₂C(O)OR⁷, —SCH₂C(O)OR⁷, —NR⁷CH₂C(O)OR⁷,—OCH₂C(O)NR¹⁰R¹¹, —SCH₂C(O)NR¹⁰R¹¹, —NR⁷CH₂C(O)NR¹⁰R¹¹, —OS(O)_(p)R⁷,—SS(O)_(p)R⁷, —S(O)_(p)OR⁷, —NR⁷S(O)_(p)R⁷, —OS(O)_(p)NR¹⁰R¹¹,—SS(O)_(p)NR¹⁰R¹¹, —NR⁷S(O)_(p)NR¹⁰R¹¹, —OS(O)_(p)OR⁷, —SS(O)_(p)OR⁷,—NR⁷S(O)_(p)OR⁷, —OC(S)R⁷, —SC(S)R⁷, —NR⁷C(S)R⁷, —OC(S)OR⁷, —SC(S)OR⁷,—NR⁷C(S)OR⁷, —OC(S)NR¹⁰R¹¹, —SC(S)NR¹⁰R¹¹, —NR⁷C(S)NR¹⁰R¹¹, —OC(NR⁷)R⁷,—SC(NR⁷)R⁷, —NR⁷C(NR⁷)R⁷, —OC(NR⁷)OR⁷, —SC(NR⁷)OR⁷, —NR⁷C(NR⁷)OR⁷,—OC(NR⁷)NR¹⁰R¹¹, —SC(NR⁷)NR¹⁰R¹¹, —NR⁷C(NR⁷)NR¹⁰R¹¹, —OP(O)(OR⁷)₂, or—SP(O)(OR⁷)₂. In a more particular aspect, R¹ and R² are independentlyselected from —OH, —OR⁹, —SH and —NHR⁷, wherein R⁹ is a C₁-C₃ alkyl. Inanother aspect, both R¹ and R² are —OH. In a further aspect, R¹ is —OR⁹;R² is —OH; and R⁹ is —CH₃ or —CH₂CH₃.

Each R⁴ and R⁵ in Formulae (I)-(IV) is independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl,aralkyl, and heteraralkyl represented by R⁴ or R⁵ is optionally andindependently substituted; or R⁴ and R⁵, taken together with thenitrogen to which they are attached, form an optionally substitutedheterocyclyl or an optionally substituted heteroaryl. In a moreparticular aspect, wherein at least one of R⁴ or R⁵ is hydrogen and theother is selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇cycloalkyl, C₅-C₇ cycloalkenyl, naphthyl, (CH₂)_(b)-triazolyl,(CH₂)_(b)-phenyl, (CH₂)_(b)-morpholinyl, (CH₂)_(b)-piperidinyl,(CH₂)_(b)-piperazinyl, (CH₂)_(b)-pyrrolidinyl, (CH₂)_(b)-imidazolidinyl,(CH₂)_(b)-pyrazolyl, (CH₂)_(b)-pyrrolyl, (CH₂)_(b)-pyridinyl,(CH₂)_(b)-pyrimidinyl, (CH₂)_(b)-pyridazinyl, (CH₂)_(b)-thienyl,(CH₂)_(b)-furanyl, (CH₂)_(b)-oxazolyl, (CH₂)_(b)-thiazolyl,(CH₂)_(b)-isoxazolyl, (CH₂)_(b)-isothiazolyl, (CH₂)_(b)-indolyl,(CH₂)_(b)-indolinyl, (CH₂)_(b)-2,3-dihydro-1H-indenyl,(CH₂)_(b)-benzoimidazolyl, (CH₂)_(b)-indazolyl, (CH₂)_(b)-3H-indazolyl,(CH₂)_(b)-benzoxazolyl, (CH₂)_(b)-benzo[1,3]dioxolyl,(CH₂)_(b)-benzofuryl, (CH₂)_(b)-benzothiazolyl,(CH₂)_(b)-benzo[d]isoxazolyl, (CH₂)_(b)-benzo[d]isothiazolyl,(CH₂)_(b)-thiazolo[4,5-c]pyridinyl, (CH₂)_(b)-thiazolo[5,4-c]pyridinyl,(CH₂)_(b)-thiazolo[4,5-b]pyridinyl, (CH₂)_(b)-thiazolo[5,4-b]pyridinyl,(CH₂)_(b)-oxazolo[4,5-c]pyridinyl, (CH₂)_(b)-oxazolo[5,4-c]pyridinyl,(CH₂)_(b)-oxazolo[4,5-b]pyridinyl, (CH₂)_(b)-oxazolo[5,4-b]pyridinyl,(CH₂)_(b)-imidazopyridinyl, (CH₂)_(b)-benzothiadiazolyl,(CH₂)_(b)-benzoxadiazolyl, (CH₂)_(b)-benzotriazolyl,(CH₂)_(b)-tetrahydroindolyl, (CH₂)_(b)-azaindolyl, (CH₂)_(b)-purinyl,(CH₂)_(b)-imidazo[4,5-a]pyridinyl, (CH₂)_(b)-imidazo[1,2-a]pyridinyl,(CH₂)_(b)-3H-imidazo[4,5-b]pyridinyl,(CH₂)_(b)-1H-imidazo[4,5-b]pyridinyl,(CH₂)_(b)-1H-imidazo[4,5-c]pyridinyl,(CH₂)_(b)-3H-imidazo[4,5-c]pyridinyl, (CH₂)_(b)-pyrrolo[2,3]pyrimidyl,(CH₂)_(b)-pyrazolo[3,4]pyrimidyl,(CH₂)_(b)-1′,3′-dihydrospiro-([1,3]dioxolane-2,2′-indene), or(CH₂)_(b)-benzo[b]thienyl, each of which is optionally and independentlysubstituted with one or more halo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl,phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl,piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, —NR¹⁰R¹¹, —OR⁷,—C(O)R⁷, —C(O)OR⁷, —C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷, —NR⁷C(O)NR¹⁰R¹¹,—S(O)_(p)R⁷, —OS(O)_(p)R⁷, or —S(O)_(p)NR¹⁰R¹¹; wherein b is an integerfrom 0 to 6. In an even more particular aspect, both R⁴ and R⁵ arehydrogen. Alternatively, R⁴ and R⁵ can be taken together with thenitrogen atom to which they are attached, form a 5-6 memberedheterocyclic ring which is optionally substituted with one or more halo,cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, pyridinyl,pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl,imidazolyl, pyrrolidinyl, —N(R¹²)₂, —OR¹², —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, —NR¹²C(O)R¹², —NR¹²C(O)N(R¹²)₂, —S(O)_(p)R¹²,—OS(O)_(p)R¹² or —S(O)_(p)N(R¹²)₂. When R⁴ is hydrogen, then R⁵ canadditionally be a lower alkyl optionally substituted with C₁-C₃ alkoxy,hydroxyl or halo.

In a further aspect in Formulae (I)-(IV), R⁴ is hydrogen and R⁵ isrepresented by:

Specific values of R⁵ for this aspect of in the invention include:

The variable s is an integer from 2 to 7; and more particularly 2 or 3.

Each R¹³ and R¹⁴ is independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl andheteroaralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteroaralkylrepresented by R¹³ and R¹⁴ is optionally and independently substitutedwith one or more halo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, phenyl,naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl,piperidinyl, imidazolyl, pyrrolidinyl, —N(R¹²)₂, —OR¹², —C(O)R¹²,—C(O)OR¹², —C(O)N(R¹²)₂, —NR¹²C(O)R¹², —NR¹²C(O)N(R¹²)₂, —S(O)_(p)R¹²,—OS(O)_(p)R¹² or —S(O)_(p)N(R¹²)₂; or R¹³ and R¹⁴, taken together withthe nitrogen atom to which they are attached, form a 5 to 6-memberedheterocyclyl or heteroaryl ring which is optionally substituted with oneor more halo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl,pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl,imidazolyl, pyrrolidinyl, —N(R¹²)₂, —OR¹², —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, —NR¹²C(O)R¹², —NR¹²C(O)N(R¹²)₂, —S(O)_(p)R¹²,—OS(O)_(p)R¹² or —S(O)_(p)N(R¹²)₂. Another particular aspect of theinvention is when R¹³ and R¹⁴ are independently C₁-C₆ alkyl, C₂-C₆alkenyl, C₃-C₇ cycloalkyl, C₅-C₆ cycloalkenyl, phenyl, benzyl, naphthyl,pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl,imidazolyl or pyrrolidinyl, each optionally substituted with one or morehalo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, phenyl, —N(R¹²)₂, —OR¹²,—C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂ or —NR¹²C(O)R¹². Further, this aspectincludes when at least one of R¹³ or R¹⁴ is a lower alkyl, optionallysubstituted with one or more halo, —N(R¹²)₂, —OR¹², —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂ or —NR¹²C(O)R¹². Additional values of R¹³ and R¹⁴ includewhen both R¹³ and R¹⁴ are lower alkyl optionally substituted with one ormore halo, —N(R¹²)₂, —OR¹², —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂ or—NR¹²C(O)R¹².

Y in Formulae (I)-(IV) is O or S. More particularly, Y is O.

Each Z in Formulae (I)-(IV) is independently alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl,heteroaralkyl, halo, cyano, nitro, guanadino, alkoxy, —NR¹⁰R¹¹, —OR⁷,—C(O)R⁷, —C(O)OR⁷, —C(S)R⁷, —C(O)SR⁷, —C(S)SR⁷, —C(S)OR⁷, —C(S)NR¹⁰R¹¹,—C(NR⁷)OR⁷, —C(NR⁷)R⁷, —C(NR⁷)NR¹⁰R¹¹, —C(NR⁷)SR⁷, —OC(O)R⁷, —OC(O)OR⁷,—OC(S)OR⁷, —OC(NR⁷)OR⁷, —SC(O)R⁷, —SC(O)OR⁷, —SC(NR⁷)OR⁷, —OC(S)R⁷,—SC(S)R⁷, —SC(S)OR⁷, —OC(O)NR¹⁰R¹¹, —OC(S)NR¹⁰R¹¹, —OC(NR⁷)NR¹⁰R¹¹,—SC(O)NR¹⁰R¹¹, —SC(NR⁷)NR¹⁰R¹¹, —SC(S)NR¹⁰R¹¹, —OC(NR⁷)R⁷, —SC(NR⁷)R⁷,—C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷, —NR⁷C(S)R⁷, —NR⁷C(S)OR⁷, —NR⁷C(NR⁷)R⁷,—NR⁷C(O)OR⁷, —NR⁷C(NR⁷)OR⁷, —NR⁷C(O)NR¹⁰R¹¹, —NR⁷C(S)NR¹⁰R¹¹,—NR⁷C(NR⁷)NR¹⁰R¹¹, —S(O)_(p)R⁷, —OS(O)_(p)R⁷, —OS(O)_(p)OR⁷,—OS(O)_(p)NR¹⁰R¹¹, —S(O)_(p)OR⁷, —NR⁷S(O)_(p)R⁷, —NR⁷S(O)_(p)NR¹⁰R¹¹,—NR⁷S(O)_(p)OR⁷, —S(O)_(p)NR¹⁰R¹¹, —SS(O)_(p)R⁷, —SS(O)_(p)OR⁷,—SS(O)_(p)NR¹⁰R¹¹, —OP(O)(OR⁷)₂, or —SP(O)(OR⁷)₂, wherein the alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, heteroaralkyl represented by Z are optionally andindependently substituted. Particularly, Z is C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ thioalkoxy, C₁-C₆alkylsulfonyl, C₃-C₆ cycloalkyl, —NR¹⁰R¹¹, —C(O)R⁷, —C(O)OR⁷,—C(O)NR¹⁰R¹¹, or —NR⁷C(O)R⁷. More particularly, Z is C₁-C₄ alkyl. Moreparticularly, Z is isopropyl.

In one aspect of the present invention, each R⁷ in Formulae (I)-(IV),where present, is independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, orheteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkylrepresented by R⁷ is optionally and independently substituted. Moreparticularly, each R⁷ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, phenyl, naphthyl, benzyl,pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl,imidazolyl, pyrrolidinyl, wherein each substituent represented by R⁷,excluding hydrogen, is optionally and independently substituted by C₁-C₃alkyl, halo, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, —N(R¹²)₂, cyano, —C(O)OR¹²,—C(O)N(R¹²)₂, —C(O)R¹², —NR¹²C(O)R¹² or phenyl. More specific values ofR⁷ include hydrogen, methyl, or ethyl, each of which is independentlyand optionally substituted with methoxy, ethoxy, hydroxyl,dimethylamine, methylamine, ethylamine, diethylamine, pyrrolidinyl,morpholinyl, thiomorpholinyl, piperizinyl, 1-methylpiperizinyl,1-ethylpiperizinyl or piperidinyl.

Each R¹⁰ and R¹¹ in Formulae (I)-(IV) is independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl,aralkyl, and heteraralkyl represented by R¹⁰ or R¹¹ is optionally andindependently substituted; or R¹⁰ and R¹¹, taken together with thenitrogen to which they are attached, form an optionally substitutedheterocyclyl or an optionally substituted heteroaryl. More particularly,each R¹⁰ and R¹¹ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, phenyl, naphthyl, benzyl, pyridinyl,pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl, piperidinyl,imidazolyl, pyrrolidinyl, wherein each substituent represented by R¹⁰ orR¹¹, excluding hydrogen, is optionally and independently substituted byC₁-C₃ alkyl, halo, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, —N(R¹²)₂, cyano,—C(O)OR¹², —C(O)N(R¹²)₂, C(O)R¹², —NR¹²C(O)R¹² or phenyl; or R¹⁰ andR¹¹, taken together with the nitrogen to which they are attached, form a5-7 membered heterocyclyl or a 5-6 membered heteroaryl eachindependently and optionally substituted with C₁-C₃ alkyl, halo, C₁-C₃haloalkyl, C₁-C₃ alkoxy, —N(R¹²)₂, cyano, —C(O)OR¹², —C(O)N(R¹²)₂,C(O)R¹², —NR¹²C(O)R¹² or phenyl. Another particular embodiment is wheneach R¹⁰ and R¹¹ is independently hydrogen, methyl, ethyl, propyl,i-propyl, butyl, t-butyl, or i-butyl, wherein each is independently andoptionally substituted with methoxy, ethoxy, hydroxyl, dimethylamine,methylamine, ethylamine, diethylamine, pyrrolidinyl, morpholinyl,thiomorpholinyl, piperizinyl, 1-methylpiperizinyl, 1-ethylpiperizinyl orpiperidinyl.

R³ in Formulae (I)-(IV) is hydrogen, —X⁵⁰R⁵⁰, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, orheteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkylrepresented by R³ is optionally and independently substituted. In oneparticular embodiment, R³ is —H. In another particular embodiment, R³ isrepresented by one of the formulae below:

In the above particular values of R³, in Formulae (I)-(IV), each X,where present, is independently N or CR²¹; each R²¹ is independentlyhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halo, cyano,nitro, —NR¹⁰R¹¹, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —C(S)R⁷, —C(O)SR⁷, —C(S)OR⁷,—C(S)NR¹⁰R¹¹, —C(NR⁷)OR⁷, —C(NR⁷)R⁷, —C(NR⁷)NR¹⁰R¹¹, —C(NR⁷)SR⁷,—OC(O)R⁷, —OC(O)OR⁷, —OC(NR⁷)OR⁷, —OC(S)R⁷, —OC(O)NR¹⁰R¹¹,—OC(NR⁷)NR¹⁰R¹¹, —OC(NR⁷)R⁷, —C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷, —NR⁷C(S)OR⁷,—NR⁷C(NR⁷)R⁷, —NR⁷C(O)OR⁷, —NR⁷C(NR⁷)OR⁷, —NR⁷C(O)NR¹⁰R¹¹,—NR⁷C(NR⁷)NR¹⁰R¹¹, —OS(O)_(p)R⁷, —OS(O)_(p)OR⁷, —OS(O)_(p)NR¹⁰R¹¹,—S(O)_(p)OR⁷, —NR⁷S(O)_(p)R⁷, —NR⁷S(O)_(p)NR¹⁰R¹¹, —NR⁷S(O)_(p)OR⁷,—S(O)_(p)NR¹⁰R¹¹, or —OP(O)(OR⁷)₂, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl andheteroaralkyl represented by R²¹ is optionally and independentlysubstituted; or two adjacent R²¹ substituents, together with the atomsto which they are attached, form a cycloalkyl, heterocyclyl, aryl, orheteroaryl moiety, each of which may be optionally substituted. Moreparticularly, each R²¹ is independently alkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, halo, cyano, nitro, —NR¹⁰R¹¹, —OR⁷, —C(O)R⁷, —C(O)OR⁷,—C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷, —NR⁷C(O)NR¹⁰R¹¹, —S(O)_(p)R⁷, —OS(O)_(p)R⁷,—S(O)_(p)NR¹⁰R¹¹, wherein each alkyl, cycloalkyl, heterocyclyl, aryl,and heteroaryl represented by R²¹ is optionally and independentlysubstituted by one or more halo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl,phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl,piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, —NR¹⁰R¹¹, —OR⁷,—C(O)R⁷, —C(O)OR⁷, —C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷, —NR⁷C(O)NR¹⁰R¹¹,—S(O)_(p)R⁷, —OS(O)_(p)R⁷, —S(O)_(p)NR¹⁰R¹¹; or two adjacent R²¹substituents, together with the atoms to which they are attached, form aC₅-C₆ cycloalkyl, phenyl, 5-6 membered heterocyclyl, or 5-6 memberedheteroaryl moiety, each of which may be optionally substituted by one ormore by one or more halo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, phenyl,naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl,piperidinyl, —NR¹⁰R¹¹, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —C(O)NR¹⁰R¹¹,—NR⁷C(O)R⁷, —NR⁷C(O)NR¹⁰R¹¹, —S(O)_(p)R⁷, —OS(O)_(p)R⁷, or—S(O)_(p)NR¹⁰R¹¹. In a further particular value, each R²¹ isindependently C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl, halo, cyano, nitro,—N(R¹²)₂, —OR¹², —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, —NR¹²C(O)R¹² or—S(O)_(p)R¹², wherein each substituent represented by R²¹ is optionallyand independently substituted by one or more halo, cyano, C₁-C₃ alkyl,C₁-C₃ haloalkyl, phenyl, —N(R¹²)₂ or —OR¹².

R¹² is hydrogen or C₁-C₃ alkyl. The variable p is an integer from 0 to2.

The variable m in Formulae (I)-(IV) is an integer from 0 to 2.Particularly, m is 0 or 1. More particularly, m is 0.

B is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,aryl, heteroaryl, aralkyl, heteroaralkyl, halo, cyano, nitro, guanadino,—NR¹⁰R¹¹, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —C(S)R⁷, —C(O)SR⁷, —C(S)OR⁷,—C(S)NR¹⁰R¹¹, —C(NR⁷)OR⁷, —C(NR⁷)R⁷, —C(NR⁷)NR¹⁰R¹¹, —C(NR⁷)SR⁷,—OC(O)R⁷, —OC(O)OR⁷, —OC(S)OR⁷, —OC(NR⁷)OR⁷, —SC(O)R⁷, —SC(O)OR⁷,—SC(NR⁷)OR⁷, —OC(S)R⁷, —SC(S)R⁷, —SC(S)OR⁷, —OC(O)NR¹⁰R¹¹,—OC(S)NR¹⁰R¹¹, —OC(NR⁷)NR¹⁰R¹¹, —SC(O)NR¹⁰R¹¹, —SC(NR⁷)NR¹⁰R¹¹,—SC(S)NR¹⁰R¹¹, —OC(NR⁷)R⁷, —SC(NR⁷)R⁷, —C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷,—NR⁷C(S)R⁷, —NR⁷C(S)OR⁷, —NR⁷C(NR⁷)R⁷, —NR⁷C(O)OR⁷, —NR⁷C(NR⁷)OR⁷,—NR⁷C(O)NR¹⁰R¹¹, —NR⁷C(S)NR¹⁰R¹¹, —NR⁷C(NR⁷)NR¹⁰R¹¹, —S(O)_(p)R⁷,—OS(O)_(p)R⁷, —OS(O)_(p)OR⁷, —OS(O)_(p)NR¹⁰R¹¹, —S(O)_(p)OR⁷,—NR⁷S(O)_(p)R⁷, —NR⁷S(O)_(p)NR¹⁰R¹¹, —NR⁷S(O)_(p)OR⁷, —S(O)_(p)NR¹⁰R¹¹,—SS(O)_(p)R⁷, —SS(O)_(p)OR⁷, —SS(O)_(p)NR¹⁰R¹¹, —OP(O)(OR⁷)₂, or—SP(O)(OR⁷)₂, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteroaralkylrepresented by B is optionally and independently substituted.Particularly, B is halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, —OR⁷, —SR⁷,—NR¹⁰R¹¹, —NR¹⁰C(O)R⁷, —S(O)_(p)NR¹⁰R¹¹, —C(O)NR¹⁰R¹¹ or—NR¹⁰C(O)NR¹⁰R¹¹, each of which is independently and optionallysubstituted by one or more halo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl,phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl,piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, —NR¹⁰R¹¹, —OR⁷,—C(O)R⁷, —C(O)OR⁷, —C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷, —NR⁷C(O)NR¹⁰R¹¹,—S(O)_(p)R⁷, —OS(O)_(p)R², —S(O)_(p)NR¹⁰R¹¹. More particularly, B is aheterocyclyl, cycloalkyl, heteroaryl, aryl, alkyl, alkenyl, alkynyl,halo, cyano, nitro, —OR⁷, —SR⁷, —NR¹⁰R¹¹, —NR¹⁰C(O)R⁷, —S(O)_(p)NR¹⁰R¹¹,—C(O)NR¹⁰R¹¹, —NR¹⁰C(O)NR¹⁰R¹¹, wherein each heterocyclyl, cycloalkyl,heteroaryl, aryl, alkyl, alkenyl and alkynyl represented by B isoptionally and independently substituted by one or more by one or moreC₁-C₃ alkyl, halo, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, —N(R¹²)₂, cyano,—C(O)OR¹², —C(O)N(R¹²)₂, C(O)R¹², —NR¹²C(O)R¹² or phenyl. Moreparticularly, B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, naphthyl,morpholinyl, thiomorpholinyl, 4-oxo-thiomorpholin-1-yl,4,4-dioxo-thiomorpholin-1-yl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,pyridinyl, 1-oxo-pyridinyl, furanyl, benzo[1,3]dioxolyl,benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl,isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl,imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl,benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl,azaindolyl, imidazopyridyl, quinazolinyl, purinyl,pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl,imidazo[1,2-a]pyridyl, or benzothienyl, each of which is optionally andindependently substituted with one or more halo, cyano, C₁-C₃ alkyl,C₁-C₃ haloalkyl, phenyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl,piperizinyl, piperidinyl, —N(R¹²)₂, —OR¹², —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, —NR¹²C(O)R¹², —NR¹²C(O)N(R¹²)₂, —S(O)_(p)R¹²,—OS(O)_(p)R¹², or —S(O)_(p)N(R¹²)₂. Even more particularly, B iscyclopentyl, cyclohexyl, phenyl, naphthyl, morpholinyl, thiomorpholinyl,4-oxo-thiomorpholin-1-yl, 4,4-dioxo-thiomorpholin-1-yl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, pyridinyl,1-oxo-pyridinyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl,thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl,benzofuryl, indolizinyl, tetrazolyl, benzimidazolyl, benzothiazolyl,benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl,quinazolinyl, purinyl, or benzothienyl, each of which is optionally andindependently substituted with one or more C₁-C₃ alkyl, C₁-C₃ haloalkyl,C₁-C₃ haloalkoxy, halo, cyano, —OR¹², —N(R¹²)₂, —C(O)(R¹²), —C(O)O(R¹²),—C(O)N(R¹²)₂, or —N(R¹²)C(O)(R¹²). Another particular value for B iswhen B is morpholinyl, thiomorpholinyl, pyrrolidinyl, piperizinyl,4-oxo-thiomorpholin-1-yl, or 4,4-dioxo-thiomorpholin-1-yl, each of whichmay be optionally and independently substituted with one or more C₁-C₃alkyl, —OR¹², —N(R¹²)₂ or halo. In the most particular embodiment, B ismorpholinyl or B is pyrrolidinyl.

The variable n in Formulae (I)-(IV) is an integer from 0 to 3, and thevariable q in Formulae (I)-(IV) is an integer from 0 to 3. Moreparticularly, n can be 0 when q is 1, n is 0 when q is 2; n is 0 when qis 3, n is 0 when q is 0, n is 1 when q is 0, n is 1 when q is 1, n is 1when q is 2, n is 1 when q is 3, n is 2 when q is 0, n is 2 when q is 1,n is 2 when q is 2, n is 2 when q is 3, n is 3 when q is 0, n is 3 whenq is 1, n is 3 when q is 2, or n is 3 when q is 3.

An additional value of R³ in Formulae (I)-(IV) is represented by thefollowing formula:

In this value of R³, the symbol

represents either a single or a double bond; X⁴¹ is CR⁴⁴, C(R⁴⁴)₂, O, S,N or NR⁴²; Y⁴⁰ is N, NR⁴², CR⁴³ or C(R⁴³)₂; and Y⁴², for eachoccurrence, is independently N, C or CR⁴⁵. R⁴² is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, heteraralkyl, —C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷,—C(O)NR¹⁰R¹¹, —S(O)_(p)R⁷, —S(O)_(p)OR⁷, or —S(O)_(p)NR¹⁰R¹¹, whereineach alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,aryl, heteroaryl, aralkyl and heteraralkyl represented by R⁴² isoptionally and independently substituted by one or more halo, cyano,C₁-C₃ alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, pyridinyl, pyrrolyl,pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl,pyrrolidinyl, —NR¹⁰R¹¹, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —C(O)NR¹⁰R¹¹,—NR⁷C(O)R⁷, —NR⁷C(O)NR¹⁰R¹¹, —S(O)_(p)R⁷, —OS(O)_(p)R⁷,—S(O)_(p)NR¹⁰R¹¹. Each R⁴³ and R⁴⁴ is independently hydrogen, —OH,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, heteraralkyl, halo, cyano, nitro, guanadino,—C(O)R⁷, —C(O)OR⁷, —OC(O)R⁷, —C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷, —SR⁷,—S(O)_(p)R⁷, —OS(O)_(p)R⁷, —S(O)_(p)OR⁷, —NR⁷S(O)_(p)R⁷,—S(O)_(p)NR¹⁰R¹¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkylrepresented by R⁴³ and R⁴⁴ is optionally and independently substitutedby one or more halo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, phenyl,naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, piperizinyl,piperidinyl, imidazolyl, pyrrolidinyl, —NR¹⁰R¹¹, —OR⁷, —C(O)R⁷,—C(O)OR⁷, —C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷, —NR⁷C(O)NR¹⁰R¹¹, —S(O)_(p)R⁷,—OS(O)_(p)R⁷, —S(O)_(p)NR¹⁰R¹¹; or two R⁴³ substituents, or R⁴³ and R⁴⁴,taken together with the atom(s) to which they are attached, form acycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl, each ofwhich may be optionally substituted by one or more halo, cyano, C₁-C₃alkyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, pyridinyl, pyrrolyl,pyrimidinyl, morpholinyl, piperizinyl, piperidinyl, imidazolyl,pyrrolidinyl, —NR¹⁰R¹¹, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —C(O)NR¹⁰R¹¹,—NR⁷C(O)R⁷, —NR⁷C(O)NR¹⁰R¹¹, —S(O)_(p)R⁷, —OS(O)_(p)R⁷, or—S(O)_(p)NR¹⁰R¹¹. Each R⁴⁵ is independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteraralkyl,halo, cyano, nitro, guanadino, —NR¹⁰R¹¹, —OR⁷, —C(O)R⁷, —C(O)OR⁷,—OC(O)R⁷, —C(O)NR¹⁰R¹¹, —NR⁸C(O)R⁷, —S(O)_(p)R⁷, —OS(O)_(p)R⁷,—S(O)_(p)OR⁷, —NR⁸S(O)_(p)R⁷, and —S(O)_(p)NR¹⁰R¹¹, and wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, and heteraralkyl represented by R⁴⁵ is optionallyand independently substituted by one or more halo, cyano, C₁-C₃ alkyl,C₃-C₆ cycloalkyl, phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl,morpholinyl, piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl,—NR¹⁰R¹¹, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —C(O)NR¹⁰R¹¹, —NR⁷C(O)R⁷,—NR⁷C(O)NR¹⁰R¹¹, —S(O)_(p)R⁷, —OS(O)_(p)R⁷, or —S(O)_(p)NR¹⁰R¹¹; and pis 0, 1 or 2.

Specific values of R³ within the scope of the formula directly above,include when R³ is indolyl, indolinyl, 2,3-dihydro-1H-indenyl,benzoimidazolyl, indazolyl, 3H-indazolyl, benzoxazolyl,benzo[1,3]dioxolyl, benzofuryl, benzothiazolyl, benzo[d]isoxazolyl,benzo[d]isothiazolyl, thiazolo[4,5-c]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,thiazolo[5,4-b]pyridinyl, oxazolo[4,5-c]pyridinyl,oxazolo[5,4-c]pyridinyl, oxazolo[4,5-b]pyridinyl,oxazolo[5,4-b]pyridinyl, imidazopyridinyl, benzothiadiazolyl,benzoxadiazolyl, benzotriazolyl, tetrahydroindolyl, azaindolyl, purinyl,imidazo[4,5-a]pyridinyl, imidazo[1,2-a]pyridinyl,3H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-b]pyridinyl,1H-imidazo[4,5-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl,pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl,1′,3′-dihydrospiro-([1,3]dioxolane-2,2′-indene), or benzo[b]thienyl,wherein each group represented by R³ can be independently and optionallysubstituted by one or more halo, cyano, C₁-C₃ alkyl, C₃-C₆ cycloalkyl,phenyl, naphthyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl,piperizinyl, piperidinyl, imidazolyl, pyrrolidinyl, —N(R¹²)₂, —OR¹²,—C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, —NR¹²C(O)R¹², —NR¹²C(O)N(R¹²)₂,—S(O)R¹², —OS(O)_(p)R¹² or —S(O)_(p)N(R¹²)₂.

A further aspect of the invention provides compounds according toFormulae (V) and (VI), wherein R³ is an optionally substituted indolyl,as shown below:

as well as pharmaceutically acceptable salts thereof, wherein, forformulae (V) and (VI), wherein the variables, where present, are asdefined for compounds according to Formulae (I)-(IV). In a particularvalue for Formula (VI), R⁴⁵ is halo, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃haloalkyl, C₁-C₃ haloalkoxy, or C₁-C₃ alkyl sulfanyl and R⁴² ishydrogen, C₁-C₃ alkyl, C₁-C₃ alkyl sulfonyl or C₁-C₃ alkylcarbonyl.

A. Definitions

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term “alkyl” means a saturated, straight chain orbranched, non-cyclic hydrocarbon having from 1 to 10 carbon atoms.Representative straight chain alkyls include methyl, ethyl, n-propyl,n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl;while representative branched alkyls include isopropyl, sec-butyl,isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl,2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl,2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl,2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl,4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl,3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, and the like. Theterm “(C₁-C₆)alkyl” means a saturated, straight chain or branched,non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Alkyl groupsincluded in compounds of this invention may be optionally substitutedwith one or more substituents.

As used herein, the term “alkenyl” means a straight chain or branched,non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having atleast one carbon-carbon double bond. Representative straight chain andbranched (C₂-C₁₀)alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl,isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl, and the like. Alkenyl groups included in compounds of theinvention may be optionally substituted with one or more substituents.

As used herein, the term “alkynyl” means a straight chain or branched,non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having atleast one carbon-carbon triple bond. Representative straight chain andbranched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl,1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl,2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl,2-decynyl, 9-decynyl, and the like. Alkynyl groups included in compoundsof the invention may be optionally substituted with one or moresubstituents.

As used herein, the term “cycloalkyl” means a saturated, mono- orpolycyclic, non-aromatic hydrocarbon having from 3 to 20 carbon atoms.Representative cycloalkyls include cyclopropyl, 1-methylcyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, octahydropentalenyl, and the like. Cycloalkylgroups included in compounds of the invention may be optionallysubstituted with one or more substituents.

As used herein, the term “cycloalkenyl” means a mono- or polycyclic,non-aromatic hydrocarbon having at least one carbon-carbon double bondin the cyclic system and having from 3 to 20 carbon atoms.Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl,cyclodecadienyl, 1,2,3,4,5,8-hexahydronaphthalenyl, and the like.Cycloalkenyl groups included in compounds of the invention may beoptionally substituted with one or more substituents.

As used herein, the term “alkylene” refers to an alkyl group that hastwo points of attachment. The term “(C₁-C₆)alkylene” refers to analkylene group that has from one to six carbon atoms. Straight chain(C₁-C₆)alkylene groups are preferred. Non-limiting examples of alkylenegroups include methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), isopropylene (—CH₂CH(CH₃)—), and the like. Alkylenegroups included in compounds of this invention may be optionallysubstituted with one or more substituents.

As used herein, the term “lower” refers to a group having up to fouratoms. For example, a “lower alkyl” refers to an alkyl radical havingfrom 1 to 4 carbon atoms, “lower alkoxy” refers to “O—(C₁-C₄)alkyl and a“lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynylradical having from 2 to 4 carbon atoms.

As used herein, the term “haloalkyl” means an alkyl group, in which oneor more, including all, the hydrogen radicals are replaced by a halogroup(s), wherein each halo group is independently selected from F, —Cl,—Br, and —I. For example, the term “halomethyl” means a methyl in whichone to three hydrogen radical(s) have been replaced by a halo group.Representative haloalkyl groups include trifluoromethyl, bromomethyl,1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

As used herein, an “alkoxy” is an alkyl group which is attached toanother moiety via an oxygen linker. Alkoxy groups included in compoundsof this invention may be optionally substituted with one or moresubstituents.

As used herein, a “haloalkoxy” is a haloalkyl group which is attached toanother moiety via an oxygen linker.

As used herein, the term an “aromatic ring” or “aryl” means a mono- orpolycyclic hydrocarbon, containing from 6 to 15 carbon atoms, in whichat least one ring is aromatic. Examples of suitable aryl groups include,but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl,azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties suchas 5,6,7,8-tetrahydronaphthyl. Aryl groups included in compounds of thisinvention may be optionally substituted with one or more substituents.In one embodiment, the aryl group is a monocyclic ring, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryl.”

As used herein, the term “aralkyl” means an aryl group that is attachedto another group by a (C₁-C₆)alkylene group. Representative aralkylgroups include benzyl, 2-phenyl-ethyl, naphth-3-yl-methyl and the like.Aralkyl groups included in compounds of this invention may be optionallysubstituted with one or more substituents.

As used herein, the term “heterocyclyl” means a monocyclic or apolycyclic, saturated or unsaturated, non-aromatic ring or ring systemwhich typically contains 5- to 20-members and at least one heteroatom. Aheterocyclic ring system can contain saturated ring(s) or unsaturatednon-aromatic ring(s), or a mixture thereof. A 3- to 10-memberedheterocycle can contain up to 5 heteroatoms, and a 7- to 20-memberedheterocycle can contain up to 7 heteroatoms. Typically, a heterocyclehas at least one carbon atom ring member. Each heteroatom isindependently selected from nitrogen, which can be oxidized (e.g., N(O))or quaternized, oxygen and sulfur, including sulfoxide and sulfone. Theheterocycle may be attached via any heteroatom or carbon atom.Representative heterocycles include morpholinyl, thiomorpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatommay be substituted with a protecting group known to those of ordinaryskill in the art, for example, a nitrogen atom may be substituted with atert-butoxycarbonyl group. Furthermore, the heterocyclyl included incompounds of this invention may be optionally substituted with one ormore substituents. Only stable isomers of such substituted heterocyclicgroups are contemplated in this definition.

As used herein, the term “heteroaromatic”, “heteroaryl”, or like terms,means a monocyclic or a polycyclic, unsaturated radical containing atleast one heteroatom, in which at least one ring is aromatic. Polycyclicheteroaryl rings must contain at least one heteroatom, but not all ringsof a polycyclic heteroaryl moiety must contain heteroatoms. Eachheteroatom is independently selected from nitrogen, which can beoxidized (e.g., N(O)) or quaternized, oxygen and sulfur, includingsulfoxide and sulfone. Representative heteroaryl groups include pyridyl,1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl,pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, atriazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl,benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl,benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl,indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl,purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl,imidazo[1,2-a]pyridyl, and benzothienyl. In one embodiment, theheteroaromatic ring is selected from 5-8 membered monocyclic heteroarylrings. The point of attachment of a heteroaromatic or heteroaryl ringmay be at either a carbon atom or a heteroatom. Heteroaryl groupsincluded in compounds of this invention may be optionally substitutedwith one or more substituents. As used herein, the term “(C₅)heteroaryl”means an heteroaromatic ring of 5 members, wherein at least one carbonatom of the ring is replaced with a heteroatom, such as, for example,oxygen, sulfur or nitrogen. Representative (C₅)heteroaryls includefuranyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and thelike. As used herein, the term “(C₆)heteroaryl” means an aromaticheterocyclic ring of 6 members, wherein at least one carbon atom of thering is replaced with a heteroatom such as, for example, oxygen,nitrogen or sulfur. Representative (C₆)heteroaryls include pyridyl,pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, and the like.

As used herein, the term “heteroaralkyl” means a heteroaryl group thatis attached to another group by a (C₁-C₆)alkylene. Representativeheteroaralkyls include 2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl,imidazol-4-yl-methyl, and the like. Heteroaralkyl groups included incompounds of this invention may be optionally substituted with one ormore substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

As used herein the term “heteroalkyl” means a straight or branched alkylgroup wherein one or more of the internal carbon atoms in the chain isreplaced by a heteroatom. For example, a heteroalkyl is represented bythe formula —[CH₂]_(x)—Z—[CH₂]_(y)[CH₃], wherein x is a positive integerand y is zero or a positive integer, Z is O, NR, S, S(O), or S(O)₂, andwherein replacement of the carbon atom does not result in a unstablecompound. Heteroalkyl groups included in compounds of this invention maybe optionally substituted with one or more substituents.

Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, andheteroaralkyl groups include are those substituents which form a stablecompound of the invention without significantly adversely affecting thereactivity or biological activity of the compound of the invention.Examples of substituents for an alkyl, alkylene, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, andheteroaralkyl include an alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteraralkyl,heteroalkyl, alkoxy, (each of which can be optionally and independentlysubstituted), —C(O)NR²⁸R²⁹, —C(S)NR²⁸R²⁹, —C(NR³²)NR²⁸R²⁹, —NR³³C(O)R³¹,—NR³³C(S)R³¹, —NR³³C(NR³²)R³¹, halo, —OR³³, cyano, nitro, —C(O)R³³,—C(S)R³³, —C(NR³²)R³³, —NR²⁸R²⁹, —C(O)OR³³, —C(S)OR³³, —C(NR³²)OR³³,—OC(O)R³³, —OC(S)R³³, —OC(NR³²)R³³, —NR³⁰C(O)NR²⁸R²⁹, —NR³³C(S)NR²⁸R²⁹,—NR³³C(NR³²)NR²⁸R²⁹, —OC(O)NR²⁸R²⁹, —OC(S)NR²⁸R²⁹, —OC(NR³²)NR²⁸R²⁹,—NR³³C(O)OR³¹, —NR³³C(S)OR³¹, —NR³³C(NR³²)OR³¹, —S(O)_(p)R³³,—OS(O)_(p)R³³, —NR³³S(O)_(p)R³³, —S(O)_(p)NR²⁸R²⁹, —OS(O)_(p)NR²⁸R²⁹,—NR³³S(O)_(p)NR²⁸R²⁹, guanadino, —C(O)SR³¹, —C(S)SR³¹, —C(NR³²)SR³¹,—OC(O)OR³¹, —OC(S)OR³¹, —OC(NR³²)OR³¹, —SC(O)R³³, —SC(O)OR³¹,—SC(NR³²)OR³¹, —SC(S)R³³, —SC(S)OR³¹, —SC(O)NR²⁸R²⁹, —SC(NR³²)NR²⁸R²⁹,—SC(S)NR²⁸R²⁹, —SC(NR³²)R³³, —OS(O)_(p)OR³¹, —S(O)_(p)OR³¹,—NR³⁰S(O)_(p)OR³¹, —SS(O)_(p)R³³, —SS(O)_(p)OR³¹, —SS(O)_(p)NR²⁸R²⁹,—OP(O)(OR³¹)₂, or —SP(O)(OR³¹)₂. In addition, any saturated portion ofan alkyl, cycloalkyl, alkylene, heterocyclyl, alkenyl, cycloalkenyl,alkynyl, aralkyl and heteroaralkyl groups, may also be substituted with═O, ═S, or ═N—R³².

Each R²⁸ and R²⁹ is independently H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, orheteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteroalkylrepresented by R²⁸ or R²⁹ is optionally and independently substituted.

Each R³¹ and R³³ is independently H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, orheteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkylrepresented by R³¹ or R³³ is optionally and independently unsubstituted.

Each R³² is independently H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteraralkyl,—C(O)R³³, —C(O)NR²⁸R²⁹, —S(O)_(p)R³³, or —S(O)^(p)NR²⁸R²⁹, wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl and heteraralkyl represented by R³² is optionallyand independently substituted.

The variable p is 0, 1 or 2.

When a heterocyclyl, heteroaryl or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent, thenitrogen may be oxidized or a quaternary nitrogen.

As used herein, the terms “subject”, “patient” and “mammal” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey, or a mammal),preferably a mammal including a non-primate (e.g., a cow, pig, horse,sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate(e.g., a monkey, chimpanzee and a human), and more preferably a human.In one embodiment, the subject is a non-human animal such as a farmanimal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat,guinea pig or rabbit). In a preferred embodiment, the subject is ahuman.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups, such as, for example, carboxy, hydroxy,thiol and amino moieties, also include corresponding protectedderivatives thereof. “Protected derivatives” are those compounds inwhich a reactive site or sites are blocked with one ore more protectinggroups. Examples of suitable protecting groups for hydroxyl groupsinclude benzyl, methoxymethyl, allyl, trimethylsilyl,tert-butyldimethylsilyl, acetate, and the like. Examples of suitableamine protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl,tert-butyl, benzyl and fluorenylmethyloxy-carbonyl (Fmoc). Examples ofsuitable thiol protecting groups include benzyl, tert-butyl, acetyl,methoxymethyl and the like. Other suitable protecting groups are wellknown to those of ordinary skill in the art and include those found inT. W. GREENE, PROTECTING GROUPS IN ORGANIC SYNTHESIS, (John Wiley &Sons, Inc., 1981).

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of Formulae (I)-(VI), or Table 1, or apharmaceutically acceptable salt thereof. Also included in the scope ofthe present invention are a solvate, clathrate, hydrate, polymorph orprodrug, or protected derivative of a compound of Formulae (I)-(VI). Theterm “compound(s) of this invention” also includes anhydrous forms. Ananhydrous form encompasses a composition of matter that is devoid ofwater or any other solvent.

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. According to this invention, the chemical structuresdepicted herein, including the compounds of this invention, encompassall of the corresponding compounds' enantiomers, diastereomers andgeometric isomers, that is, both the stereochemically pure form (e.g.,geometrically pure, enantiomerically pure, or diastereomerically pure)and isomeric mixtures (e.g., enantiomeric, diastereomeric and geometricisomeric mixtures). In some cases, one enantiomer, diastereomer orgeometric isomer will possess superior activity or an improved toxicityor kinetic profile compared to other isomers. In those cases, suchenantiomers, diastereomers and geometric isomers of compounds of thisinvention are preferred.

When a disclosed compound is named or depicted by structure, it is to beunderstood that solvates (e.g., hydrates) of the compound or apharmaceutically acceptable salt thereof is also included. “Solvates”refer to crystalline forms wherein solvent molecules are incorporatedinto the crystal lattice during crystallization. Solvates may includewater or nonaqueous solvents such as ethanol, isopropanol, DMSO, aceticacid, ethanolamine and ethyl acetate. When water is the solvent moleculeincorporated into the crystal lattice of a solvate, it is typicallyreferred to as a “hydrate”. Hydrates include stoichiometric hydrates aswell as compositions containing variable amounts of water.

When a disclosed compound is named or depicted by structure, it is to beunderstood that the compound, including solvates thereof, may exist incrystalline forms, non-crystalline forms or a mixture thereof. Thecompounds or solvates may also exhibit polymorphism (i.e., the capacityto occur in different crystalline forms). These different crystallineforms are typically known as “polymorphs.” It is to be understood thatwhen named or depicted by structure, the disclosed compounds andsolvates (e.g., hydrates) also include all polymorphs thereof.Polymorphs have the same chemical composition but differ in packing,geometrical arrangement and other descriptive properties of thecrystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra and X-ray powder diffractionpatterns, which may be used for identification. One of ordinary skill inthe art will appreciate that different polymorphs may be produced, forexample, by changing or adjusting the conditions used in crystallizingthe compound. For example, changes in temperature, pressure or solventmay result in different polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

When a disclosed compound is named or depicted by structure, it is to beunderstood that clathrates (“inclusion compounds”) of the compound orits pharmaceutically acceptable salt, solvate or polymorph, are alsoincluded. “Clathrate” means a compound of the present invention, or asalt thereof, in the form of a crystal lattice that contains spaces(e.g., channels) that have a guest molecule trapped within (e.g., asolvent or water).

As used herein, and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may become active upon suchreaction under biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds ofFormulae (I)-(VI) or Table 1 that comprise biohydrolyzable moieties suchas biohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides andbiohydrolyzable phosphate analogues. Other examples of prodrugs includederivatives of compounds of Formulae (I)-(VI) or Table 1 that comprise—NO, —NO₂, —ONO, or —ONO₂ moieties. Prodrugs can typically be preparedusing well-known methods, such as those described by 1 BURGER'SMEDICINAL CHEMISTRY AND DRUG DISCOVERY, (Manfred E. Wolff Ed., 5^(th)ed. (1995)) 172-178, 949-982.

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as improvedwater solubility, improved circulating half-life in the blood (e.g.,because of reduced metabolism of the prodrug), improved uptake, improvedduration of action, or improved onset of action; or 2) is itselfbiologically inactive but is converted in vivo to a biologically activecompound. Examples of biohydrolyzable amides include, but are notlimited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides,and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, “Hsp90” includes each member of the family of heat shockproteins having a mass of about 90-kiloDaltons. For example, in humansthe highly conserved Hsp90 family includes the cytosolic Hsp90α andHsp90β isoforms, as well as GRP94, which is found in the endoplasmicreticulum, and HSP75/TRAP1, which is found in the mitochondrial matrix.

The term “c-Kit” or “c-Kit kinase” refers to a membrane receptor proteintyrosine kinase which is preferably activated upon binding Stem CellFactor (SCF) to its extracellular domain. Yarden, et al., Embo. J.,(1987) 11:3341-3351; Qiu, et al., Embo. J., (1988) 7:1003-1011. The fulllength amino acid sequence of a c-Kit kinase preferably is as set forthin Yarden, et al.; and Qiu, et al., which are incorporated by referenceherein in their entirety, including any drawings. Mutant versions ofc-Kit kinase are encompassed by the term “c-Kit” or “c-Kit kinase” andinclude those that fall into two classes: (1) having a single amino acidsubstitution at codon 816 of the human c-Kit kinase, or its equivalentposition in other species (Ma, et al., J. Invest Dermatol., (1999)112:165-170), and (2) those which have mutations involving the putativejuxtamembrane z-helix of the protein (Ma, et al., J. Biol. Chem., (1999)274:13399-13402). Both of these publications are incorporated byreference herein in their entirety, including any drawings.

As used herein, “BCR-ABL” is a fusion protein that results from thetranslocation of gene sequences from c-ABL protein tyrosine kinase onchromosome 9 into BCR sequences on chromosome 22 producing thePhiladelphia chromosome. A schematic representation of human BCR, ABLand BCR-ABL can be seen in FIG. 1 of U.S. patent application Ser. No.10/193,651, filed on Jul. 9, 2002, the entire teachings of which areincorporated herein by reference. Depending on the breaking point in theBCR gene, BCR-ABL fusion proteins can vary in size from 185-230 kDa butthey must contain at least the OLI domain from BCR and the TK domainfrom ABL for transforming activity. The most common BCR-ABL geneproducts found in humans are P230 BCR-ABL, P210 BCR-ABL and P190BCR-ABL. P210 BCR-ABL is characteristic of CML and P190 BCR-ABL ischaracteristic of ALL.

FLT3 kinase is a tyrosine kinase receptor involved in the regulation andstimulation of cellular proliferation. Gilliland, et al., Blood (2002),100:1532-42. The FLT3 kinase has five immunoglobulin-like domains in itsextracellular region, as well as an insert region of 75-100 amino acidsin the middle of its cytoplasmic domain. FLT3 kinase is activated uponthe binding of the FLT3 ligand which causes receptor dimerization.Dimerization of the FLT3 kinase by FLT3 ligand activates theintracellular kinase activity as well as a cascade of downstreamsubstrates including Stat5, Ras, phosphatidylinositol-3-kinase (PI3K),Erk2, Akt, MAPK, SHC, SHP2 and SHIP. Rosnet, et al., Acta Haematol.(1996), 95:218; Hayakawa, et al., Oncogene (2000), 19:624; Mizuki, etal., Blood (2000), 96:3907; Gilliand, et al., Curr. Opin. Hematol.(2002), 9: 274-81. Both membrane-bound and soluble FLT3 ligand bind,dimerize, and subsequently activate the FLT3 kinase.

Normal cells that express FLT3 kinase include immature hematopoieticcells, typically CD34+ cells, placenta, gonads and brain. Rosnet, etal., Blood (1993), 82:1110-19; Small, et al., Proc. Natl. Acad. Sci.U.S.A. (1994), 91:459-63; Rosnet, et al., Leukemia (1996), 10:238-48.However, efficient stimulation of proliferation via FLT3 kinasetypically requires other hematopoietic growth factors or interleukins.FLT3 kinase also plays a critical role in immune function through itsregulation of dendritic cell proliferation and differentiation. McKenna,et al., Blood (2000), 95:3489-497.

Numerous hematologic malignancies express FLT3 kinase, the mostprominent of which is AML. Yokota, et al., Leukemia (1997), 11:1605-09.Other FLT3 expressing malignancies include B-precursor cell acutelymphoblastic leukemias, myelodysplastic leukemias, T-cell acutelymphoblastic leukemias, and chronic myelogenous leukemias. Rasko, etal., Leukemia (1995), 9:2058-66.

FLT3 kinase mutations associated with hematologic malignancies areactivating mutations. In other words, the FLT3 kinase is constitutivelyactivated without the need for binding and dimerization by FLT3 ligand,and therefore stimulates the cell to grow continuously. Two types ofactivating mutations have been identified: internal tandem duplications(ITDs) and point mutation in the activating loop of the kinase domain.As used herein, the term “FLT3 kinase” refers to both wild type FLT3kinase and mutant FLT3 kinases, such as FLT3 kinases that haveactivating mutations.

Compounds provided herein are useful in treating conditionscharacterized by inappropriate FLT3 activity, such as proliferativedisorders. Inappropriate FLT3 activity includes, but is not limited to,enhanced FLT3 activity resulting from increased or de novo expression ofFLT3 in cells, increased FLT3 expression or activity and FLT3 mutationsresulting in constitutive activation. The existence of inappropriate orabnormal FLT3 ligand and FLT3 levels or activity can be determined usingwell known methods in the art. For example, abnormally high FLT3 levelscan be determined using commercially available ELISA kits. FLT3 levelscan also be determined using flow cytometric analysis,immunohistochemical analysis and in situ hybridization techniques.

“Epidermal growth factor receptor” or “EGFR”, as used herein, means anyepidermal growth factor receptor (EGFR) protein, peptide, or polypeptidehaving EGFR or EGFR family activity (e.g., Her1, Her2, Her3 and/orHer4), such as encoded by EGFR Genbank Accession Nos. shown in Table Iof U.S. patent application Ser. No. 10/923,354, filed on Aug. 20, 2004,or any other EGFR transcript derived from a EGFR gene and/or generatedby EGFR translocation. The term “EGFR” is also meant to include otherEGFR protein, peptide, or polypeptide derived from EGFR isoforms (e.g.,Her1, Her2, Her3 and/or Her4), mutant EGFR genes, splice variants ofEGFR genes, and EGFR gene polymorphisms.

As used herein, a “proliferative disorder” or a “hyperproliferativedisorder,” and other equivalent terms, means a disease or medicalcondition involving pathological growth of cells. Proliferativedisorders include cancer, smooth muscle cell proliferation, systemicsclerosis, cirrhosis of the liver, adult respiratory distress syndrome,idiopathic cardiomyopathy, lupus erythematosus, retinopathy, (e.g.,diabetic retinopathy or other retinopathies), cardiac hyperplasia,reproductive system associated disorders such as benign prostatichyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis,fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis and desmoidtumors. Non-cancerous proliferative disorders also includehyperproliferation of cells in the skin such as psoriasis and its variedclinical forms, Reiter's syndrome, pityriasis rubra pilaris,hyperproliferative variants of disorders of keratinization (e.g.,actinic keratosis, senile keratosis), scleroderma, and the like.

Smooth muscle cell proliferation includes hyperproliferation of cells inthe vasculature, for example, intimal smooth muscle cell hyperplasia,restenosis and vascular occlusion, particularly stenosis followingbiologically- or mechanically-mediated vascular injury, e.g., vascularinjury associated with angioplasty. Moreover, intimal smooth muscle cellhyperplasia can include hyperplasia in smooth muscle other than thevasculature, e.g., bile duct blockage, bronchial airways of the lung inpatients with asthma, in the kidneys of patients with renal interstitialfibrosis, and the like.

In a preferred embodiment, the proliferative disorder is cancer. Cancersthat can be treated by the methods of the present invention include, butare not limited to human sarcomas and carcinomas, e.g., fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acutemyelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic,monocytic and erythroleukemia); chronic leukemia (chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia); andpolycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin'sdisease), multiple myeloma, Waldenstrobm's macroglobulinemia and heavychain disease.

Other examples of leukemias include acute and/or chronic leukemias,e.g., lymphocytic leukemia, e.g., as exemplified by the p388 (murine)cell line, large granular lymphocytic leukemia, and lymphoblasticleukemia; T-cell leukemias, e.g., T-cell leukemia, as exemplified by theCEM, Jurkat, and HSB-2 (acute), YAC-1(murine) cell lines, T-lymphocyticleukemia, and T-lymphoblastic leukemia; B-cell leukemia, e.g., asexemplified by the SB (acute) cell line, and B-lymphocytic leukemia;mixed cell leukemias, e.g., B- and T-cell leukemia and B- andT-lymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia,myelocytic leukemia, e.g., as exemplified by the HL-60 (promyelocyte)cell line, and myelogenous leukemia, e.g., as exemplified by theK562(chronic) cell line; neutrophilic leukemia; eosinophilic leukemia;monocytic leukemia, e.g., as exemplified by the THP-1(acute) cell line;myelomonocytic leukemia; Naegeli-type myeloid leukemia; andnonlymphocytic leukemia. Other examples of leukemias are described inChapter 60 of THE CHEMOTHERAPY SOURCEBOOK (Michael C. Perry Ed.,Williams & Williams (1992)) and Section 36 of HOLLAND FRIE CANCERMEDICINE (Bast et al. Eds., 5th ed., B.C. Decker Inc. (2000)).

In one embodiment, the disclosed method is believed to be particularlyeffective in treating a subject with non-solid tumors such as multiplemyeloma. In another embodiment, the disclosed method is believed to beparticularly effective against T-cell leukemia, e.g., as exemplified byJurkat and CEM cell lines; B-cell leukemia, e.g., as exemplified by theSB cell line; promyelocytes, e.g., as exemplified by the HL-60 cellline; uterine sarcoma, e.g., as exemplified by the MES-SA cell line;monocytic leukemia, e.g., as exemplified by the THP-1(acute) cell line;and lymphoma, e.g., as exemplified by the U937 cell line.

In one embodiment, the disclosed method is believed to be particularlyeffective in treating a subject with non-Hodgkin's lymphoma (NHL).Lymphomas are generally classified as either Hodgkin's disease (HD) ornon-Hodgkin's lymphomas. NHL differs from HD by the absence ofReed-Sternberg cells. The course of NHL is less predictable than HD andis more likely to spread to areas beyond the lymph nodes. NHL can befurther divided into B-cell NHL and T-cell NHL, each of which can befurther categorized into a variety of different subtypes. For example,B-cell NHL includes Burkitt's lymphoma, follicular lymphoma, diffuselarge B-cell lymphoma, nodal marginal zone B-cell lymphoma, plasma cellneoplasms, small lymphocytic lymphoma/chronic lymphocytic leukemia,mantle cell lymphoma, extranodal marginal zone B-cell lymphoma andlymphoplamacytic lymphoma/Waldenstrom macroglobulinemia. T-cell NHLincludes anaplastic large-cell lymphoma, precursor-T-cell lymphoblasticleukemia/lymphoma, unspecified peripheral T-cell lymphoma, acutelymphoblastic leukemia/lymphoma, angioimmunoblastic T-cell lymphoma andmycosis fungoides.

Without wishing to be bound by any theory, it is believed that thecompounds of the invention are useful for treating NHLs, includingB-cell and T-cell NHLs, because Hsp90 is upregulated in many NHLs. Inparticular, in a survey of 412 cases of NHL in B-cell NHL, Hsp90 wasfound to be moderately to strongly over expressed in all cases ofBurkitt's lymphoma (5/5, 100%), and in a subset of follicular lymphoma(17/28, 61%), diffuse large B-cell lymphoma (27/46, 59%), nodal marginalzone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%),small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%),mantle cell lymphoma (12/38, 32%) and lymphoplamacyticlymphoma/Waldenstrom macroglobulinemia (3/10, 30%). In addition, inT-cell NHL, Hsp90 was found to be moderately to strongly over expressedin a subset of anaplastic large-cell lymphoma (14/24, 58%),precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%),unspecified peripheral T-cell lymphoma (8/43, 23%) andangioimmunoblastic T-cell lymphoma (2/17, 12%). Valbuena, et al., ModernPathology (2005), 18:1343-1349.

Some of the disclosed methods can be particularly effective at treatingsubjects whose cancer has become “drug resistant” or “multi-drugresistant”. A cancer which initially responded to an anti-cancer drugbecomes resistant to the anti-cancer drug when the anti-cancer drug isno longer effective in treating the subject with the cancer. Forexample, many tumors will initially respond to treatment with ananti-cancer drug by decreasing in size or even going into remission,only to develop resistance to the drug. Drug resistant tumors arecharacterized by a resumption of their growth and/or reappearance afterhaving seemingly gone into remission, despite the administration ofincreased dosages of the anti-cancer drug. Cancers that have developedresistance to two or more anti-cancer drugs are said to be “multi-drugresistant”. For example, it is common for cancers to become resistant tothree or more anti-cancer agents, often five or more anti-cancer agentsand at times ten or more anti-cancer agents.

As used herein, the term “c-Kit associated cancer” refers to a cancerwhich has aberrant expression and/or activation of c-Kit. c-Kitassociated cancers include leukemias, mast cell tumors, small cell lungcancer, testicular cancer, some cancers of the gastrointestinal tractand some cancers of the central nervous system. In addition, c-Kit hasbeen implicated in playing a role in carcinogenesis of the femalegenital tract (Inoue, et al., Cancer Res., (1994) 54(11):3049-3053),sarcomas of neuroectodermal origin (Ricotti, et al., Blood, (1998)91:2397-2405), and Schwann cell neoplasia associated withneurofibromatosis (Ryan, et al., J. Neuro. Res., (1994) 37:415-432).

Other anti-proliferative or anti-cancer therapies may be combined withthe compounds of this invention to treat proliferative diseases andcancer. Other therapies or anti-cancer agents that may be used incombination with the inventive anti-cancer agents of the presentinvention include surgery, radiotherapy (including, but not limited to,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, and systemic radioactive isotopes),endocrine therapy, biologic response modifiers (including, but notlimited to, interferons, interleukins, and tumor necrosis factor (TNF)),hyperthermia and cryotherapy, agents to attenuate any adverse effects(e.g., antiemetics), and other approved chemotherapeutic drugs.

In one embodiment, compounds of the invention are vascular targetingagents. In one aspect, compounds of the invention are effective forblocking, occluding, or otherwise disrupting blood flow in“neovasculature.” In one aspect, the invention provides a noveltreatment for diseases involving the growth of new blood vessels(“neovasculature”), including, but not limited to: cancer; infectiousdiseases; autoimmune disorders; benign tumors, e.g. hemangiomas,acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas;artheroscleric plaques; ocular angiogenic diseases, e.g., diabeticretinopathy, retinopathy of prematurity, macular degeneration, cornealgraft rejection, neovascular glaucoma, retrolental fibroplasia,rubeosis, retinoblastoma, persistent hyperplastic vitreous syndrome,choroidal neovascularization, uvietis and Pterygia (abnormal bloodvessel growth) of the eye; rheumatoid arthritis; psoriasis; warts;allergic dermatitis; blistering disease; Karposi sarcoma; delayed woundhealing; endometriosis; uterine bleeding; ovarian cysts; ovarianhyperstimulation; vasculogenesis; granulations; hypertrophic scars(keloids); nonunion fractures; scleroderma; trachoma; vascularadhesions; vascular malformations; DiGeorge syndrome; hereditaryhemorrhagic telangiectasia (HHT or Osler-Webber Syndrome); transplantarteriopathy; restinosis; obesity; myocardial angiogenesis; coronarycollaterals; cerebral collaterals; arteriovenous malformations; ischemiclimb angiogenesis; primary pulmonary hypertension; asthma; nasal polyps;inflammatory bowel disease; periodontal disease; ascites; peritonealadhesions; plaque neovascularization; telangiectasia; hemophiliacjoints; synovitis; osteomyelitis; osteophyte formation; angiofibroma;fibromuscular dysplasia; wound granulation; Crohn's disease; andatherosclerosis. Vascular targeting can be demonstrated by any methodknown to those skilled in the art, such as the method described hereinin Examples 8 and 9.

As used herein, the term “angiogenesis” refers to a fundamental processof generating new blood vessels in tissues or organs. Angiogenesis isinvolved with or associated with many diseases or conditions, including,but not limited to: cancer; ocular neovascular disease; age-relatedmacular degeneration; diabetic retinopathy, retinopathy of prematurity;corneal graft rejection; neovascular glaucoma; retrolental fibroplasias;epidemic keratoconjunctivitis; Vitamin A deficiency; contact lensoverwear; atopic keratitis; superior limbic keratitis; pterygiumkeratitis sicca; sjogrens; acne rosacea; warts; eczema; phylectenulosis;syphilis; Mycobacteria infections; lipid degeneration; chemical burns;bacterial ulcers; fungal ulcers; Herpes simplex infections; Herpeszoster infections; protozoan infections; Kaposi's sarcoma; Mooren'sulcer; Terrien's marginal degeneration; mariginal keratolysis;rheumatoid arthritis; systemic lupus; polyarteritis; trauma; Wegener'ssarcoidosis; scleritis; Stevens-Johnson disease; pemphigoid; radialkeratotomy; corneal graph rejection; sickle cell anemia; sarcoid;syphilis; pseudoxanthoma elasticum; Paget's disease; vein occlusion;artery occlusion; carotid obstructive disease; chronic uveitis/vitritis;mycobacterial infections; Lyme's disease; systemic lupus erythematosis;Eales' disease; Behcet's disease; infections causing a retinitis orchoroiditis; presumed ocular histoplasmosis; Best's disease; myopia;optic pits; Stargardt's disease; pars planitis; chronic retinaldetachment; hyperviscosity syndromes; toxoplasmosis; trauma andpost-laser complications; diseases associated with rubeosis(neovasculariation of the angle); diseases caused by the abnormalproliferation of fibrovascular or fibrous tissue including all forms ofproliferative vitreoretinopathy; rheumatoid arthritis; osteoarthritis;ulcerative colitis; Crohn's disease; Bartonellosis; atherosclerosis;Osler-Weber-Rendu disease (also known as hereditary hemorrhagictelangiectasia or HHT); pulmonary hemangiomatosis; preeclampsia;endometriosis; fibrosis of the liver and of the kidney; developmentalabnormalities (organogenesis); skin discolorations (e.g., hemangioma,nevus flammeus or nevus simplex); wound healing; hypertrophic scars,i.e., keloids; wound granulation; vascular adhesions; cat scratchdisease (Rochele ninalia quintosa); ulcers (Helicobacter pylori);keratoconjunctivitis; gingivitis; periodontal disease; epulis;hepatitis; tonsillitis; obesity; rhinitis; laryngitis; tracheitis;bronchitis; bronchiolitis; pneumonia; interstitial pulmonary fibrosis;neurodermitis; thyroiditis; thyroid enlargement; endometriosis;glomerulonephritis; gastritis; inflammatory bone and cartilagedestruction; thromboembolic disease; and Buerger's disease.

The term “infection” is used herein in its broadest sense and refers toany infection, e.g., a viral infection or one caused by a microorganism,such as a bacterial infection, fungal infection or parasitic infection(e.g. protozoal, amoebic, or helminth). Examples of such infections maybe found in a number of well known texts such as GREENWOOD, D., ET AL.,MEDICAL MICROBIOLOGY (Churchill Livingstone Press, 2002); Mims, C., etal., Mims' Pathogenesis of Infectious Disease” (Academic Press, 2000);FIELDS, B. N., ET AL., FIELDS VIROLOGY (Lippincott Williams and Wilkins,2001); SANFORD, J. P., ET AL., THE SANFORD GUIDE TO ANTIMICROBIALTHERAPY, (Antimicrobial Therapy, Inc., 26th ed. 1996).

“Bacterial infections” include, but are not limited to, infectionscaused by Gram positive acteria including Bacillus cereus, Bacillusanthracis, Clostridium botulinum, Clostridium difficile, Clostridiumtetani, Clostridium perfringens, Corynebacteria diphtheriae,Enterococcus (Streptococcus D), Listeria monocytogenes, Pneumoccoccalinfections (Streptococcus pneumoniae), Staphylococcal infections andStreptococcal infections; Gram negative bacteria including Bacteroides,Bordetella pertussis, Brucella, Campylobacter infections,enterohaemorrhagic Escherichia coli (EHEC/E. coli 0157: H7),enteroinvasive Escherichia coli (EIEC), enterotoxigenic Escherichia coli(ETEC), Haemophilus influenzae, Helicobacter pylori, Klebsiellapneumoniae, Legionella spp., Moraxella catarrhalis, Neisseriagonnorrhoeae, Neisseria meningitidis, Proteus spp., Pseudomonasaeruginosa, Salmonella spp., Shigella spp., Vibrio cholera and Yersinia;acid fast bacteria including Mycobacterium tuberculosis, Mycobacteriumavium-intracellulare, Myobacterium johnei, Mycobacterium leprae,atypical bacteria, Chlamydia, Mycoplasma, Rickettsia, Spirochetes,Treponema pallidum, Borrelia recurrentis, Borrelia burgdorfii andLeptospira icterohemorrhagiae; or other miscellaneous bacteria,including Actinomyces and Nocardia.

The term “fungus” or “fungal” refers to a distinct group of eukaryotic,spore-forming organisms with absorptive nutrition and lackingchlorophyll. It includes mushrooms, molds, and yeasts. “Fungalinfections” include, but are not limited to, infections caused byAlternaria alternata, Aspergillus flavus, Aspergillus fumigatus,Aspergillus nidulans, Aspergillus niger, Aspergillus versicolor,Blastomyces dermatiditis, Candida albicans, Candida dubliensis, Candidakrusei, Candida parapsilosis, Candida tropicalis, Candida glabrata,Coccidioides immitis, Cryptococcus neoformans, Epidermophyton floccosum,Histoplasma capsulatum, Malassezia furfur, Microsporum canis, Mucorspp., Paracoccidioides brasiliensis, Penicillium marneffei, Pityrosporumovale, Pneumocystis carinii, Sporothrix schenkii, Trichophyton rubrum,Trichophyton interdigitale, Trichosporon beigelii, Rhodotorula spp.,Brettanomyces clausenii, Brettanomyces custerii, Brettanomycesanomalous, Brettanomyces naardenensis, Candida himilis, Candidaintermedia, Candida saki, Candida solani, Candida versatilis, Candidabechii, Candida famata, Candida lipolytica, Candida stellata, Candidavini, Debaromyces hansenii, Dekkera intermedia, Dekkera bruxellensis,Geotrichium sandidum, Hansenula fabiani, Hanseniaspora uvarum, Hansenulaanomala, Hanseniaspora guillermondii, Hanseniaspora vinae, Kluyveromyceslactis, Kloekera apiculata, Kluveromyces marxianus, Kluyveromycesfragilis, Metschikowia pulcherrima, Pichia guilliermodii, Pichiaorientalis, Pichia fermentans, Pichia memranefaciens, RhodotorulaSaccharomyces bayanus, Saccharomyces cerevisiae, Saccharomycesdairiensis, Saccharomyces exigus, Saccharomyces uinsporus, Saccharomycesuvarum, Saccharomyces oleaginosus, Saccharomyces boulardii,Saccharomycodies ludwigii, Schizosaccharomyces pombe, Torulasporadelbruekii, Torulopsis stellata, Zygoaccharomyces bailli andZygosaccharomyces rouxii.

Drug resistance in fungi is characterized by the failure of anantifungal therapy to control a fungal infection. “Antifungalresistance”, as used herein, refers to both intrinsic or primaryresistance, which is present before exposure to antifungal agents andsecondary or acquired resistance, which develops after exposure toantifungal therapies. Hsp90 has been shown to play a role in theevolution of drug resistance in fungi. Cowen, L., et al., EukaryoticCell, (2006) 5(12):2184-2188; Cowen, L. et al., Science, (2005)309:2185-2189. It has been shown that the key mediator of Hsp90dependent azole resistance is calcineurin, a client protein of Hsp90.Calcineurin is required for tolerating the membrane stress exerted byazole drugs. Hsp90 keeps calcineurin stable and poised for activation.In addition, it has been shown that Hsp90 is required for the emergenceof drug resistance and continued drug resistance to azoles andechinocandins.

“Parasitic infections” include, but are not limited to, infectionscaused by Leishmania, Toxoplasma, Plasmodia, Theileria, Acanthamoeba,Anaplasma, Giardia, Trichomonas, Trypanosoma, Coccidia and Babesia. Forexample, parasitic infections include those caused by Trypanosoma cruzi,Eimeria tenella, Plasmodium falciparum, Plasmodium vivax, Plasmodiumovale, Cryptosporidium parvum, Naegleria fowleri, Entamoeba histolytica,Balamuthia mandrillaris, Entameoba histolytica, Schistostoma mansoni,Plasmodium falciparum, P. vivax, P. ovale, P. malariae, P. berghei,Leishmania donovani, L. infantum, L. chagasi, L. mexicana, L.amazonensis, L. venezuelensis, L. tropics, L. major, L. minor, L.aethiopica, L. Biana braziliensis, L. (V.) guyanensis, L. (V.)panamensis, L. (V.) peruviana, Trypanosoma brucei rhodesiense, T. bruceigambiense, Giardia intestinalis, G. lambda, Toxoplasma gondii,Trichomonas vaginalis, Pneumocystis carinii, Acanthamoeba castellani, A.culbertsoni, A. polyphaga, A. healyi, (A. astronyxis), A. hatchetti, A.rhysodes, and Trichinella spiralis.

As used herein, the term “viral infection” refers to any stage of aviral infection, including incubation phase, latent or dormant phase,acute phase, and development and maintenance of immunity towards avirus. Viral infections include, but are not limited to those caused byAdenovirus, Lassa fever virus (Arenavirus), Astrovirus, Hantavirus, RiftValley Fever virus (Phlebovirus), Calicivirus, Ebola virus, MarburgVirus, Japanese encephalitis virus, Dengue virus, Yellow fever virus,Hepatitis A virus, Hepatitis C virus, Hepatitis G virus, Hepatitis Bvirus, Hepatitis D virus, Herpes simplex virus 1, Herpes simplex virus2, Cytomegalovirus, Epstein Barr virus, Varicella Zoster virus, HumanHerpesvirus 7, Human Herpesvirus 8, Influenza virus, Parainfluenzavirus, Rubella virus, Mumps virus, Morbillivirus, Measles virus,Respiratory Syncytial virus, Papillomaviruses, JC virus (Polyomavirus),BK virus (Polyomavirus), Parvovirus, Coxsackie virus (A and B),Polioviruses, Rhinoviruses, Reovirus, Rabies Virus (Lyssavirus), HumanImmunodeficiency virus 1 and 2, and Human T-cell Leukemia virus.Examples of viral infections include Adenovirus acute respiratorydisease, Lassa fever, Astrovirus enteritis, Hantavirus pulmonarysyndrome, Rift valley fever, Ebola hemorrhagic fever, Marburghemorrhagic fever, Japanese encephalitis, Dengue fever, Yellow fever,Hepatitis C, Hepatitis G, Hepatitis B, Hepatitis D, Hepatitis E, coldsores, genital sores, Cytomegalovirus infection, Mononucleosis, ChickenPox, Shingles, Human Herpesvirus infection 7, Kaposi Sarcoma, Influenza,Brochiolitis, German measles (rubeola), Mumps, Measles, Brochiolitis,Papillomas (Warts), cervical cancer, progressive multifocalleukoencephalopathy, kidney disease, Erythema infectiosum, viralmyocarditis, meninigitis, entertitis, Hepatitis, Poliomyelitis, thecommon cold, diarrhoea, Rabies, AIDS and Leukemia.

DNA topoisomerases are enzymes present in all cells that catalyzetopological changes in DNA. Topoisomerase II (“topo II”) plays importantroles in DNA replication, chromosome segregation and the maintenance ofthe nuclear scaffold in eukaryotic cells. The enzyme acts by creatingbreaks in DNA, thereby allowing the DNA strands to unravel and separate.Due to the important roles of the enzyme in dividing cells, the enzymeis a highly attractive target for chemotherapeutic agents, especially inhuman cancers. The inhibition of topo II can be determined by any methodknown in the art. See, e.g., Gadelle, D., et al., BiochemicalPharmacology, (2006), 72(10):1207-1216.

The glucocorticoid receptor is a member of the steroid hormone nuclearreceptor family which includes glucocorticoid receptors (GR), androgenreceptors (AR), mineralocorticoid receptors (MR), estrogen receptors(ER) and progesterone receptors (PR). Glucocorticoid receptors bindglucocorticoids such as cortisol, corticosterone and cortisone.

“Immunosuppression” refers to the impairment of any component of theimmune system resulting in decreased immune function. This impairmentmay be measured by any conventional means including whole blood assaysof lymphocyte function, detection of lymphocyte proliferation andassessment of the expression of T cell surface antigens. The antisheepred blood cell (SRBC) primary (IgM) antibody response assay (usuallyreferred to as the plaque assay) is one specific method. This and othermethods are described in Luster, M. I, et al., Fundam. Appl. Toxicol.(1992), 18: 200-210. Measuring the immune response to a T-cell dependentimmunogen is another particularly useful assay. Dean, J. H., et al.,Immunotoxicology: Effects of, and Responses to, Drugs and Chemicals, InPRINCIPLES AND METHODS OF TOXICOLOGY: FOURTH EDITION (A. W. Hayes, Ed.)(Taylor & Francis, Philadelphia, Pa.) (2001) 1415-1450. In oneembodiment, a decrease in the expression of glucocorticoid receptors inPBMCs indicates impairment of immune function. A patient in need ofimmunosuppression can be determined by a physician, and can includepatients with immune or inflammatory disorders. For example, patientsthat have undergone or will be undergoing an organ, tissue, bone marrowor stem cell transplantation are in need of immunosuppression to preventinflammation and/or rejection of the transplanted organ or tissue. Oneembodiment of the invention provides treatment of a patient in need ofimmunosuppression, comprising administering an effective amount of acompound of the invention to the patient.

The compounds of this invention can be used to treat subjects withimmune disorders. As used herein, the term “immune disorder”, and liketerms, means a disease, disorder or condition caused by the immunesystem of a subject, including autoimmune disorders. Immune disordersinclude those diseases, disorders or conditions that have an immunecomponent and those that are substantially or entirely immunesystem-mediated. Autoimmune disorders are those wherein the subject'sown immune system mistakenly attacks itself, thereby targeting thecells, tissues and/or organs of the subject's own body. For example, theautoimmune reaction is directed against the nervous system in multiplesclerosis and the gut in Crohn's disease. In other autoimmune disorders,such as systemic lupus erythematosus (lupus), affected tissues andorgans may vary among subjects with the same disease. One subject withlupus may have affected skin and joints, whereas another may haveaffected skin, kidney and lungs. Ultimately, damage to certain tissuesby the immune system may be permanent, as with destruction ofinsulin-producing cells of the pancreas in Type 1 diabetes mellitus.Specific autoimmune disorders that may be ameliorated using thecompounds and methods of this invention include without limitation,autoimmune disorders of the nervous system (e.g., multiple sclerosis,myasthenia gravis, autoimmune neuropathies, such as Guillain-Barré, andautoimmune uveitis); autoimmune disorders of the blood (e.g., autoimmunehemolytic anemia, pernicious anemia and autoimmune thrombocytopenia);autoimmune disorders of the blood vessels (e.g., temporal arteritis,anti-phospholipid syndrome, vasculitides such as Wegener'sgranulomatosis and Behcet's disease); autoimmune disorders of the skin(e.g., psoriasis, dermatitis herpetiformis, pemphigus vulgaris andvitiligo); autoimmune disorders of the gastrointestinal system (e.g.,Crohn's disease, ulcerative colitis, primary biliary cirrhosis andautoimmune hepatitis); autoimmune disorders of the endocrine glands(e.g., Type 1 or immune-mediated diabetes mellitus, Grave's disease.Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, andautoimmune disorder of the adrenal gland); and autoimmune disorders ofmultiple organs including connective tissue and musculoskeletal systemdiseases (e.g., rheumatoid arthritis, systemic lupus erythematosus,scleroderma, polymyositis, dermatomyositis, spondyloarthropathies suchas ankylosing spondylitis and Sjogren's syndrome). In addition, otherimmune system mediated diseases, such as graft-versus-host disease andallergic disorders, are also included in the definition of immunedisorders herein. Because a number of immune disorders are caused byinflammation, there is some overlap between disorders that areconsidered immune disorders and inflammatory disorders. For the purposeof this invention, in the case of such an overlapping disorder, it maybe considered either an immune disorder or an inflammatory disorder.

As used herein, the term “allergic disorder” means a disease, conditionor disorder associated with an allergic response against normallyinnocuous substances. These substances may be found in the environment,such as indoor air pollutants and aeroallergens, or they may benon-environmental, such as those causing dermatological or foodallergies. Allergens can enter the body through a number of routes,including by inhalation, ingestion, contact with the skin or injection(including by insect sting). Many allergic disorders are linked toatopy, a predisposition to generate the allergic antibody IgE. BecauseIgE is able to sensitize mast cells anywhere in the body, atopicindividuals often express disease in more than one organ. For thepurpose of this invention, allergic disorders include anyhypersensitivity that occurs upon re-exposure to the sensitizingallergen, which in turn causes the release of inflammatory mediators.Allergic disorders include without limitation, allergic rhinitis (e.g.,hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitismedia, drug reactions, insect sting reactions, latex reactions,conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions,atopic dermatitis, asthma and food allergies.

As used herein, the term “asthma” means a pulmonary disease, disorder orcondition characterized by reversible airway obstruction, airwayinflammation, and increased airway responsiveness to a variety ofstimuli.

Compounds represented by any of the formulas disclosed herein can beused to treat subjects with inflammatory disorders. As used herein, an“inflammatory disorder” means a disease, disorder or conditioncharacterized by inflammation of body tissue or having an inflammatorycomponent. These include local inflammatory responses and systemicinflammation. Examples of such inflammatory disorders include:transplant rejection, including skin graft rejection; chronicinflammatory disorders of the joints, including arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory bowel diseases such as ileitis, ulcerativecolitis, Barrett's syndrome and Crohn's disease; inflammatory lungdisorders such as asthma, adult respiratory distress syndrome andchronic obstructive airway disease; inflammatory disorders of the eyeincluding corneal dystrophy, trachoma, onchocerciasis, uveitis,sympathetic ophthalmitis and endophthalmitis; chronic inflammatorydisorders of the gums, including gingivitis and periodontitis;tuberculosis; leprosy; inflammatory diseases of the kidney includinguremic complications, glomerulonephritis and nephrosis; inflammatorydisorders of the skin including sclerodermatitis, psoriasis and eczema;inflammatory diseases of the central nervous system, including chronicdemyelinating diseases of the nervous system, multiple sclerosis,AIDS-related neurodegeneration and Alzheimer's disease, infectiousmeningitis, encephalomyelitis, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis and viral or autoimmuneencephalitis; autoimmune disorders, immune-complex vasculitis, systemiclupus erythematosus (SLE); and inflammatory diseases of the heart suchas cardiomyopathy, ischemic heart disease hypercholesterolemia,atherosclerosis; as well as various other diseases with significantinflammatory components, including preeclampsia; chronic liver failure,brain and spinal cord trauma. There may also be a systemic inflammationof the body, exemplified by Gram positive or Gram negative shock,hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,for example, by a chemotherapeutic agent used in cancer chemotherapy.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt prepared from a compound of Formulae (I)-(VI) or Table 1 having anacidic functional group, such as a carboxylic acid functional group, anda pharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of Formulae (I)-(VI) or Table 1 having a basicfunctional group, such as an amine functional group, and apharmaceutically acceptable inorganic or organic acid. Suitable acidsinclude, but are not limited to, hydrogen sulfate, citric acid, aceticacid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr),hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid,isonicotinic acid, oleic acid, tannic acid, pantothenic acid, saccharicacid, lactic acid, salicylic acid, tartaric acid, bitartratic acid,ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid,gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamicacid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,pamoic acid and p-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more pharmaceuticallyacceptable solvent molecules to one of the compounds of Formulae(I)-(VI) or Table 1. The term solvate includes hydrates, e.g.,hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and thelike.

A pharmaceutically acceptable carrier may contain inert ingredientswhich do not unduly inhibit the biological activity of the compound(s).The pharmaceutically acceptable carriers should be biocompatible, i.e.,non-toxic, non-inflammatory, non-immunogenic and devoid of otherundesired reactions upon the administration to a subject. Standardpharmaceutical formulation techniques can be employed, such as thosedescribed in REMINGTON, J. P., REMINGTON'S PHARMACEUTICAL SCIENCES (MackPub. Co., 17^(th) ed., 1985). Suitable pharmaceutical carriers forparenteral administration include, for example, sterile water,physiological saline, bacteriostatic saline (saline containing about0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution,Ringer's-lactate, and the like. Methods for encapsulating compositions,such as in a coating of hard gelatin or cyclodextran, are known in theart. See BAKER, ET AL., CONTROLLED RELEASE OF BIOLOGICAL ACTIVE AGENTS,(John Wiley and Sons, 1986).

As used herein, the term “effective amount” refers to an amount of acompound of this invention which is sufficient to reduce or amelioratethe severity, duration, progression, or onset of a disease or disorder,delay onset of a disease or disorder, retard or halt the advancement ofa disease or disorder, cause the regression of a disease or disorder,prevent or delay the recurrence, development, onset or progression of asymptom associated with a disease or disorder, or enhance or improve thetherapeutic effect(s) of another therapy. In one embodiment of theinvention, the disease or disorder is a proliferative disorder. Theprecise amount of compound administered to a subject will depend on themode of administration, the type and severity of the disease orcondition and on the characteristics of the subject, such as generalhealth, age, sex, body weight and tolerance to drugs. For example, for aproliferative disease or disorder, determination of an effective amountwill also depend on the degree, severity and type of cell proliferation.The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors.

When co-administered with other therapeutic agents, e.g., whenco-administered with an anti-cancer agent, an “effective amount” of anyadditional therapeutic agent(s) will depend on the type of drug used.Suitable dosages are known for approved therapeutic agents and can beadjusted by the skilled artisan according to the condition of thesubject, the type of condition(s) being treated and the amount of acompound of the invention being used. In cases where no amount isexpressly noted, an effective amount should be assumed. Non-limitingexamples of an effective amount of a compound of the invention areprovided herein below. In a specific embodiment, the invention providesa method of treating, managing, or ameliorating a disease or disorder,e.g. a proliferative disorder, or one or more symptoms thereof, saidmethod comprising administering to a subject in need thereof a dose ofat least 150 μg/kg, at least 250 μg/kg, at least 500 μg/kg, at least 1mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, atleast 150 mg/kg, or at least 200 mg/kg or more of one or more compoundsof the invention once every day, once every 2 days, once every 3 days,once every 4 days, once every 5 days, once every 6 days, once every 7days, once every 8 days, once every 10 days, once every two weeks, onceevery three weeks, or once a month.

The dosage of a therapeutic agent other than a compound of theinvention, which has been or is currently being used to treat, manage,or ameliorate a disease or disorder, e.g., a proliferative disorder, orone or more symptoms thereof, can be used in the combination therapiesof the invention. Preferably, the dosage of each individual therapeuticagent used in said combination therapy is lower than the dose of anindividual therapeutic agent when given independently to treat, manage,or ameliorate a disease or disorder, or one or more symptoms thereof. Inone embodiment of the invention, the disease or disorder being treatedwith a combination therapy is a proliferative disorder. In oneembodiment, the proliferative disorder is cancer. The recommendeddosages of therapeutic agents currently used for the treatment,management, or amelioration of a disease or disorder, or one or moresymptoms thereof, can obtained from any reference in the art. See, e.g.,GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF BASIS OF THERAPEUTICS9^(TH) ED, (Hardman, et al., Eds., NY:Mc-Graw-Hill (1996)); PHYSICIAN'SDESK REFERENCE 57^(TH) ED. (Medical Economics Co., Inc., Montvale, N.J.(2003)).

As used herein, the terms “treat”, “treatment” and “treating” refer tothe reduction or amelioration of the progression, severity and/orduration of a disease or disorder, delay of the onset of a disease ordisorder, or the amelioration of one or more symptoms (preferably, oneor more discernible symptoms) of a disease or disorder, resulting fromthe administration of one or more therapies (e.g., one or moretherapeutic agents such as a compound of the invention). The terms“treat”, “treatment” and “treating” also encompass the reduction of therisk of developing a disease or disorder, and the delay or inhibition ofthe recurrence of a disease or disorder. In one embodiment, the diseaseor disorder being treated is a proliferative disorder such as cancer. Inspecific embodiments, the terms “treat”, “treatment” and “treating”refer to the amelioration of at least one measurable physical parameterof a disease or disorder, such as growth of a tumor, not necessarilydiscernible by the patient. In other embodiments the terms “treat”,“treatment” and “treating” refer to the inhibition of the progression ofa disease or disorder, e.g., a proliferative disorder, either physicallyby the stabilization of a discernible symptom, physiologically by thestabilization of a physical parameter, or both. In another embodiment,the terms “treat”, “treatment” and “treating” of a proliferative diseaseor disorder refers to the reduction or stabilization of tumor size orcancerous cell count, and/or delay of tumor formation. In anotherembodiment, the terms “treat”, “treating” and “treatment” also encompassthe administration of a compound of the invention as a prophylacticmeasure to patients with a predisposition (genetic or environmental) toany disease or disorder described herein.

“Treatment of a viral infection” is meant to include aspects ofgenerating or restoring immunity of the patient's immune system, as wellas aspects of suppressing or inhibiting viral replication.

“Treatment of an immune disorder” herein refers to administering acompound represented by any of the formulas disclosed herein to asubject, who has an immune disorder, a symptom of such a disease or apredisposition towards such a disease, with the purpose to cure,relieve, alter, affect, or prevent the autoimmune disorder, the symptomof it, or the predisposition towards it.

“Treatment of an inflammatory disorder” herein refers to administering acompound or a composition of the invention to a subject who has aninflammatory disorder, a symptom of such a disorder or a predispositiontowards such a disorder, with the purpose to cure, relieve, alter,affect, or prevent the inflammatory disorder, the symptom of it, or thepredisposition towards it.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent(s) that can be used in the treatment of a disease ordisorder, e.g. a proliferative disorder, or one or more symptomsthereof. In certain embodiments, the term “therapeutic agent” refers toa compound of the invention. In certain other embodiments, the term“therapeutic agent” does not refer to a compound of the invention.Preferably, a therapeutic agent is an agent that is known to be usefulfor, or has been or is currently being used for the treatment of adisease or disorder, e.g., a proliferative disorder, or one or moresymptoms thereof.

As used herein, the term “synergistic” refers to a combination of acompound of the invention and another therapeutic agent, which, whentaken together, is more effective than the additive effects of theindividual therapies. A synergistic effect of a combination of therapies(e.g., a combination of therapeutic agents) permits the use of lowerdosages of one or more of the therapeutic agent(s) and/or less frequentadministration of said agent(s) to a subject with a disease or disorder,e.g., a proliferative disorder. The ability to utilize lower the dosageof one or more therapeutic agent and/or to administer said therapeuticagent less frequently reduces the toxicity associated with theadministration of said agent to a subject without reducing the efficacyof said therapy in the treatment of a disease or disorder. In addition,a synergistic effect can result in improved efficacy of agents in theprevention, management or treatment of a disease or disorder, e.g. aproliferative disorder. Finally, a synergistic effect of a combinationof therapies may avoid or reduce adverse or unwanted side effectsassociated with the use of either therapeutic agent alone.

As used herein, the phrase “side effects” encompasses unwanted andadverse effects of a therapeutic agent. Side effects are alwaysunwanted, but unwanted effects are not necessarily adverse. An adverseeffect from a therapeutic agent might be harmful or uncomfortable orrisky to a subject. Side effects include, but are not limited to, fever,chills, lethargy, gastrointestinal toxicities (including gastric andintestinal ulcerations and erosions), nausea, vomiting, neurotoxicities,nephrotoxicities, renal toxicities (including such conditions aspapillary necrosis and chronic interstitial nephritis), hepatictoxicities (including elevated serum liver enzyme levels),myelotoxicities (including leukopenia, myelosuppression,thrombocytopenia and anemia), dry mouth, metallic taste, prolongation ofgestation, weakness, somnolence, pain (including muscle pain, bone painand headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms,akathisia, cardiovascular disturbances and sexual dysfunction.

As used herein, the term “in combination” refers to the use of more thanone therapeutic agent. The use of the term “in combination” does notrestrict the order in which said therapeutic agents are administered toa subject with a disease or disorder, e.g., a proliferative disorder. Afirst therapeutic agent, such as a compound of the invention, can beadministered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequentto (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or12 weeks after) the administration of a second therapeutic agent, suchas an anti-cancer agent, to a subject with a disease or disorder, e.g. aproliferative disorder, such as cancer.

As used herein, the terms “therapies” and “therapy” can refer to anyprotocol(s), method(s), and/or agent(s) that can be used in theprevention, treatment, management, or amelioration of a disease ordisorder, e.g., a proliferative disorder, or one or more symptomsthereof.

A used herein, a “protocol” includes dosing schedules and dosingregimens. The protocols herein are methods of use and includetherapeutic protocols.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to a chiral center inthe molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of the invention.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or diastereomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

When administered to a subject (e.g., a non-human animal for veterinaryuse or for improvement of livestock or to a human for clinical use), thecompounds of the invention are administered in an isolated form, or asthe isolated form in a pharmaceutical composition. As used herein,“isolated” means that the compounds of the invention are separated fromother components of either: (a) a natural source, such as a plant orcell, preferably bacterial culture, or (b) a synthetic organic chemicalreaction mixture. Preferably, the compounds of the invention arepurified via conventional techniques. As used herein, “purified” meansthat when isolated, the isolate contains at least 95%, preferably atleast 98%, of a compound of the invention by weight of the isolateeither as a mixture of stereoisomers, or as a diastereomeric orenantiomeric pure isolate.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

B. The Compounds of the Invention

The present invention encompasses compounds having Formulas (I), (II),(III), (IV), (V) and (VI), those set forth in Table 1, tautomers andpharmaceutically acceptable salts thereof.

Compounds of Formulae (I)-(VI) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing proliferative disorders,such as cancer. In addition, compounds of Formulae (I)-(VI) areparticularly useful in treating cancer when given in combination withanother anti-cancer agent.

In one embodiment, the invention provides compounds of Formula (I) asset forth below:

TABLE 1 No. Compound Name Structure 1 1- (benzo[d][1,3]dioxol-5-ylmethyl)-5-(2,4- dihydroxy-5- isopropylphenyl)-N-(2-morpholinoethyl)-1H- pyrrole-2-carboxamide

2 5-(2,4-dihydroxy-5- isopropylphenyl)-N- ethyl-1-(4- methoxybenzyl)-1H-pyrrole-2-carboxamide

3 5-(2,4-dihydroxy-5- isopropylphenyl)-1-(4- (dimethylamino)phenyl)-N-ethyl-1H-pyrrole- 2-carboxamide

4 5-(2,4-dihydroxy-5- isopropylphenyl)-N- ethyl-1-(4-((4-methylpiperazin-1- yl)methyl)benzyl)-1H- pyrrole-2-carboxamide

5 5-(2,4-dihydroxy-5- isopropylphenyl)-1-(4- morpholinophenyl)-1H-pyrrole-2- carboxamide

6 5-(2,4-dihydroxy-5- isopropylphenyl)-N- ethyl-1-(4- morpholinophenyl)-1H-pyrrole-2- carboxamide

7 N-ethyl-5-(2-hydroxy- 5-isopropyl-4- methoxyphenyl)-1-(4-morpholinophenyl)- 1H-pyrrole-2- carboxamide

8 5-(5-chloro-2,4- dihydroxyphenyl)-N- ethyl-1-(4- morpholinophenyl)-1H-pyrrole-2- carboxamide

9 5-(5-chloro-2-hydroxy- 4-methoxyphenyl)-N- ethyl-1-(4-morpholinophenyl)- 1H-pyrrole-2- carboxamide

10 5-(2,4-dihydroxy-5- isopropylphenyl)-1-(4- (morpholinomethyl)phenyl)-1H-pyrrole-2- carboxamide

11 5-(2,4-dihydroxy-5- isopropylphenyl)-N- ethyl-1-(4-(morpholinomethyl) phenyl)-1H-pyrrole-2- carboxamide

12 N-ethyl-5-(2-hydroxy- 5-isopropyl-4- methoxyphenyl)-1-(4-(morpholinomethyl) phenyl)-1H-pyrrole-2- carboxamide

13 5-(5-chloro-2,4- dihydroxyphenyl)-N- ethyl-1-(4- (morpholinomethyl)phenyl)-1H-pyrrole-2- carboxamide

14 5-(5-chloro-2-hydroxy- 4-methoxyphenyl)-N- ethyl-1-(4-(morpholinomethyl) phenyl)-1H-pyrrole-2- carboxamide

15 5-(2,4-dihydroxy-5- isopropylphenyl)-1-(4- (pyrrolidin-1-ylmethyl)phenyl)-1H- pyrrole-2-carboxamide

16 5-(2,4-dihydroxy-5- isopropylphenyl)-N- ethyl-1-(4-(pyrrolidin-1-ylmethyl)phenyl)- 1H-pyrrole-2- carboxamide

17 N-ethyl-5-(2-hydroxy- 5-isopropyl-4- methoxyphenyl)-1-(4-(pyrrolidin-1- ylmethyl)phenyl)-1H- pyrrole-2-carboxamide

18 5-(5-chloro-2,4- dihydroxyphenyl)-N- ethyl-1-(4-(pyrrolidin-1-ylmethyl)phenyl)- 1H-pyrrole-2- carboxamide

19 5-(5-chloro-2-hydroxy- 4-methoxyphenyl)-N- ethyl-1-(4-(pyrrolidin-1-ylmethyl)phenyl)- 1H-pyrrole-2- carboxamide

20 1-(4- ((diethylamino)methyl) phenyl)-5-(2,4- dihydroxy-5-isopropylphenyl)-1H- pyrrole-2-carboxamide

21 1-(4- ((diethylamino)methyl) phenyl)-5-(2,4- dihydroxy-5-isopropylphenyl)-N- ethyl-1H-pyrrole-2- carboxamide

22 1-(4- ((diethylamino)methyl) phenyl)-N-ethyl-5-(2-hydroxy-5-isopropyl-4- methoxyphenyl)-1H- pyrrole-2-carboxamide

23 5-(5-chloro-2,4- dihydroxyphenyl)-1-(4- ((diethylamino)methyl)phenyl)-N-ethyl-1H- pyrrole-2-carboxamide

24 5-(5-chloro-2-hydroxy- 4-methoxyphenyl)-1- (4- ((diethylamino)methyl)phenyl)-N-ethyl-1H- pyrrole-2-carboxamide

25 5-(2,4-dihydroxy-5- isopropylphenyl)-N- isopropyl-1-(4-morpholinophenyl)- 1H-pyrrole-2- carboxamide

26 5-(2,4-dihydroxy-5- isopropylphenyl)-N- isopropyl-1-(4-(morpholinomethyl) phenyl)-1H-pyrrole-2- carboxamide

27 5-(2,4-dihydroxy-5- isopropylphenyl)-N- isopropyl-1-(4-(pyrrolidin-1- ylmethyl)phenyl)-1H- pyrrole-2-carboxamide

28 1-(4- ((diethylamino)methyl) phenyl)-5-(2,4- dihydroxy-5-isopropylphenyl)-N- isopropyl-1H-pyrrole- 2-carboxamide

29 5-(2-hydroxy-5- isopropyl-4- methoxyphenyl)-N- isopropyl-1-(4-(pyrrolidin-1- ylmethyl)phenyl)-1H- pyrrole-2-carboxamide

30 5-(2,4-dihydroxy-5- isopropylphenyl)-1-(4- morpholinophenyl)-N-(2-(pyrrolidin-1- yl)ethyl)-1H-pyrrole-2- carboxamide

31 N-cyclopentyl-5-(2,4- dihydroxy-5- isopropylphenyl)-1-(4-(morpholinomethyl) phenyl)-1H-pyrrole-2- carboxamide

32 N-cyclohexyl-5-(2,4- dihydroxy-5- isopropylphenyl)-1-(4-(pyrrolidin-1- ylmethyl)phenyl)-1H- pyrrole-2-carboxamide

33 1-(4- ((diethylamino)methyl) phenyl)-5-(2,4- dihydroxy-5-isopropylphenyl)-N-(2- morpholinoethyl)-1H- pyrrole-2-carboxamide

34 N-(2- (diethylamino)ethyl)-5- (2-hydroxy-5- isopropyl-4-methoxyphenyl)-1-(4- (pyrrolidin-1- ylmethyl)phenyl)-1H-pyrrole-2-carboxamide

35 5-(2,4-dihydroxy-5- isopropylphenyl)-N- ethyl-1-(4- methylbenzyl)-1H-pyrrole-2-carboxamide

36 1-(4- ((diethylamino)methyl) benzyl)-5-(2,4- dihydroxy-5-isopropylphenyl)-N- ethyl-1H-pyrrole-2- carboxamide

37 5-(2,4-dihydroxy-5- isopropylphenyl)-N- ethyl-1-(4-(morpholinomethyl) benzyl)-1H-pyrrole-2- carboxamide

38 5-(2,4-dihydroxy-5- isopropylphenyl)-N- ethyl-1-(4-(pyrrolidin-1-ylmethyl)benzyl)- 1H-pyrrole-2- carboxamide

39 1- (benzo[d][1,3]dioxol- 5-ylmethyl)-5-(2,4- dihydroxy-5-isopropylphenyl)-N- ethyl-1H-pyrrole-2- carboxamide

40 5-(5-chloro-2,4- dihydroxyphenyl)-1-(4- methylbenzyl)-1H-pyrrole-2-carboxamide

41 5-(2,4-dihydroxy-5- isopropylphenyl)-1-(4- ((dimethylamino)methyl)benzyl)-N- isopropyl-1H-pyrrole- 2-carboxamide

42 5-(2,4-dihydroxy-5- isopropylphenyl)-N- isopropyl-1-(4-(morpholinomethyl) benzyl)-1H-pyrrole-2- carboxamide

43 5-(2,4-dihydroxy-5- isopropylphenyl)-N- isopropyl-1-(4-(pyrrolidin-1- ylmethyl)benzyl)-1H- pyrrole-2-carboxamide

44 1- (benzo[d][1,3]dioxo]- 5-ylmethyl)-5-(2,4- dihydroxy-5-isopropylphenyl)-N- isopropyl-1H-pyrrole- 2-carboxamide

45 5-(5-chloro-2,4- dihydroxyphenyl)-N- cyclopentyl-1-(4-methylbenzyl)-1H- pyrrole-2-carboxamide

46 N-cyclohexyl-5-(2,4- dihydroxy-5- isopropylphenyl)-1-(4-((dimethylamino) methyl)benzyl)-1H-pyrrole- 2-carboxamide

47 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2- morpholinoethyl)-1-(4-(morpholinomethyl) benzyl)-1H-pyrrole-2- carboxamide

48 5-(2,4-dihydroxy-5- isopropylphenyl)-N-(2- (pyrrolidin-1-yl)ethyl)-1-(4-(pyrrolidin-1- ylmethyl)benzyl)-1H- pyrrole-2-carboxamide

49 1- (benzo[d][1,3]dioxol- 5-ylmethyl)-5-(2,4- dihydroxy-5-isopropylphenyl)-N-(1- methylpiperidin-4-yl)- 1H-pyrrole-2- carboxamide

In certain instances, tautomeric forms of a disclosed compound exist. Itis to be understood that when a compound is represented by a structuralformula herein, all other tautomeric forms which may exist for thecompound are encompassed the structural formula. Compounds representedby formulas disclosed herein that can form analogous tautomericstructures are also preferred.

Similarly, prodrugs, i.e. compounds which can be metabolized orhydrolyzed in vivo to a compound of the present invention areencompassed by the present description. For example, the followingembodiments of a compound of the present invention can be produced invivo in the following reaction:

One skilled in the art will understand that other hydrolyzableprotecting groups can be employed with the compounds of the presentinvention to obtain prodrugs encompassed by the present description.

C. Methods for Making Compounds of the Invention

Compounds of the invention can be obtained via standard, well-knownsynthetic methodology. See e.g., MARCH, J., ADVANCED ORGANIC CHEMISTRY:REACTIONS MECHANISMS AND STRUCTURE, (4th ed., (1992)).

Reactive functional groups can be protected during one or more reactionstep, and then deprotected to restore the original functionality.Examples of suitable protecting groups for hydroxyl groups includebenzyl, methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl,acetate, and the like. Examples of suitable amine protecting groupsinclude benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl andfluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiolprotecting groups include benzyl, tert-butyl, acetyl, methoxymethyl andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. GREENE,PROTECTING GROUPS IN ORGANIC SYNTHESIS (John Wiley & Sons (1981)).

STEP-1 involves a Suzuki coupling between a bromopyrrole derivative anda protected boronic acid derivative of resorcinol, thus yielding theproduct 3. STEP-2 involves two parts—1) the hydrolysis of the ester tothe acid and 2) the formation of the ethyl amide 4 using EDC, DMAP andethyl amine. STEP-3 exemplifies the debenzylation (deprotection) step toyield the final product 5.

D. Uses of Compounds of the Invention

The present invention is directed to therapies which involveadministering one of more compounds of the invention, and pharmaceuticalcompositions comprising said one or more compounds to a subject,preferably a human subject, to inhibit the activity of Hsp90 to treat adisease or disorder, such as a proliferative disorder, or one or moresymptoms thereof. In one embodiment, the proliferative disorder iscancer.

In another embodiment, the present invention is directed to treatingcancers in which aberrant expression and/or activation of c-Kit has beenimplicated as a contributing factor. The method comprises administeringto a subject an effective amount of a compound represented by Formulae(I)-(VI) or a compound shown in Table 1.

In one embodiment, the present invention is directed to treating cancersin which expression of BCR-ABL has been implicated as a contributingfactor. The method comprises administering to a subject an effectiveamount of a compound represented by Formulae (I)-(VI) or a compoundshown in Table 1.

In one embodiment, the present invention is directed to treating cancersin which aberrant expression and/or activation of FLT3 has beenimplicated as a contributing factor. The method comprises administeringto a subject an effective amount of a compound represented by Formulae(I)-(VI) or a compound shown in Table 1.

In one embodiment, the present invention is directed to treating cancersin which aberrant expression and/or activation of EGFR has beenimplicated as a contributing factor. The method comprises administeringto a subject an effective amount of a compound represented by Formulae(I)-(VI) or a compound shown in Table 1.

In one embodiment, the present invention is directed to treating cancersin which Hsp90 is over expressed, as compared with normal cells. Themethod comprises administering to a subject an effective amount of acompound represented by Formulae (I)-(VI) or a compound shown inTable 1. Examples of cancers in which Hsp90 is over expressed includediffuse large B-cell lymphomas (DLBCL).

In one aspect, the invention provides a method of inhibiting theactivity of Hsp90 in a cell, comprising administering to the cell aneffective amount of a compound represented by Formulae (I)-(VI) or acompound shown in Table 1. In one embodiment, the compound isadministered to a cell in a subject, preferably a mammal, and morepreferably a human.

In another aspect, the invention provides a method of treating aproliferation disorder in a subject, comprising administering to thesubject an effective amount of a compound represented by Formulae(I)-(VI) or a compound shown in Table 1. In one embodiment, the compoundis administered to a mammal to treat a proliferative disorder. Inanother embodiment, the mammal is a human. In another embodiment, theproliferation disorder is cancer. In another embodiment, the compound isadministered with one or more additional therapeutic agents. In apreferred embodiment, the additional therapeutic agent(s) is ananti-cancer agent.

In another aspect, the invention provides a method for treating a c-Kitassociated cancer in a subject, comprising administering to the subjectan effective amount of a compound represented by Formulae (I)-(VI) or acompound shown in Table 1. In one embodiment the subject is a mammal,preferably a human. In one embodiment, the compound is administered to ahuman to treat the c-Kit associated cancer. In another embodiment, thecompound is administered with one or more additional therapeutic agents.In a preferred embodiment, the one or more additional therapeutic agentsare anti-cancer agents.

In another aspect, the invention provides a method for treating aBCR-ABL associated cancer in a subject, comprising administering to thesubject an effective amount of a compound represented by Formulae(I)-(VI) or a compound shown in Table 1. In one embodiment the subjectis a mammal, preferably a human. In one embodiment, the compound isadministered to a human to treat or prevent the BCR-ABL associatedcancer. In another embodiment, the compound is administered with one ormore additional therapeutic agents. In a preferred embodiment, the oneor more additional therapeutic agents are anti-cancer agents.

In another aspect, the invention provides a method for treating a FLT3associated cancer in a subject, comprising administering to the subjectan effective amount of a compound represented by Formulae (I)-(VI) or acompound shown in Table 1. In one embodiment the subject is a mammal,preferably a human. In one embodiment, the compound is administered to ahuman to treat the FLT3 associated cancer. In another embodiment, thecompound is administered with one or more additional therapeutic agents.In a preferred embodiment, the one or more additional therapeutic agentsare anti-cancer agents.

In another aspect, the invention provides a method for treating an EGFRassociated cancer in a subject, comprising administering to the subjectan effective amount of a compound represented by Formulae (I)-(VI) or acompound shown in Table 1. In one embodiment the subject is a mammal,preferably a human. In one embodiment, the compound is administered to ahuman to treat the EGFR associated cancer. In another embodiment, thecompound is administered with one or more additional therapeutic agents.In a preferred embodiment, the one or more additional therapeutic agentsare anti-cancer agents.

In another aspect, the invention provides a method for treating a cancerin a subject which is characterized by the upregulation of Hsp90,compared to normal cells of the same type, comprising administering tothe subject an effective amount of a compound represented by Formulae(I)-(VI) or a compound shown in Table 1. In one embodiment the subjectis a mammal, preferably a human. In one embodiment, the compound isadministered to a human to treat or prevent the cancer associated withthe upregulation of Hsp90. In another embodiment, the cancer associatedwith the upregulation of Hsp90 is DLBCL. In another embodiment, thecompound is administered with one or more additional therapeutic agents.In a preferred embodiment, the one or more additional therapeutic agentsare anti-cancer agents.

In another aspect, the invention provides a method for treating orinhibiting angiogenesis in a subject in need thereof, comprisingadministering to the subject an effective amount of a compoundrepresented by Formulae (I)-(VI) or a compound shown in Table 1.

In another aspect, the invention provides a method of blocking,occluding, or otherwise disrupting blood flow in neovasculature in asubject, comprising contacting the neovasculature with an effectiveamount of a compound represented by Formulae (I)-(VI) or a compoundshown in Table 1. In one aspect, the neovasculature is in a subject andblood flow in the neovasculature is blocked, occluded, or otherwisedisrupted in the subject by administering to the subject an effectiveamount of a compound represented by Formulae (I)-(VI) or a compoundshown in Table 1. In one aspect, the subject is human.

The present invention provides a method for treating an infection in asubject in need thereof, comprising administering an effective amount ofa compound represented by Formulae (I)-(VI), or a compound shown inTable 1. In one embodiment the subject is a mammal, preferably a human.In one aspect, the invention is directed to a method of treating afungal infection. In one aspect, the invention is directed to a methodof treating a yeast infection. In one aspect, the invention is directedto a method of treating a yeast infection caused by Candida yeast.

In another embodiment the invention is directed to a method of treatingfungal drug resistance a subject in need thereof, comprisingadministering an effective amount of a compound represented by Formulae(I)-(VI), or a compound shown in Table 1. In one aspect, the fungal drugresistance is associated with an azole drug. In another aspect, thefungal drug resistance is associated with a non-azole fungal drug. Inone aspect, the non-azole drug is an echinocandin. In one aspect, theazole fungal drug is ketoconazole, miconazole, fluconazole,itraconazole, posaconazole, ravuconazole, voriconazole, clotrimazole,econazole, oxiconazole, sulconazole, terconazole, butoconazole,isavuconazole or tioconazole. In one aspect, the azole fungal drug isfluconazole.

In one aspect, the invention is directed to a method of treating abacterial infection in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound accordingto Formulae (I)-(VI) or a compound shown in Table 1. In one aspect, theinvention is directed to a method of treating a bacterial infectioncaused by Gram positive bacteria. In one aspect, the invention isdirected to a method of treating a bacterial infection caused by Gramnegative bacteria.

In one aspect, the invention is directed to a method of treating a viralinfection in a subject in need thereof, comprising administering to thesubject an effective amount of a compound according to Formulae (I)-(VI)or a compound shown in Table 1. In one aspect, the invention is directedto a method of treating a viral infection caused by an influenza virus,a herpes virus, a hepatitis virus, or an HIV virus. In one aspect, theinvention is directed to a method of treating a viral infection causedby influenza A virus, herpes simplex virus type 1, hepatitis C virus,hepatitis B virus, HIV-1 virus, or Epstein-Barr Virus.

In one aspect, the invention is directed to a method of treating aparasitic infection in a subject in need thereof, comprisingadministering to the subject an effective amount of a compound accordingto Formulae (I)-(VI) or a compound shown in Table 1. In one aspect, theinvention is directed to a method of treating a protozoal infection. Inone aspect, the invention is directed to a method of treating aninfection caused by plasmodium falciparum or trypsanosoma cruzi. In oneaspect, the invention is directed to a method of treating an infectioncaused by a leishmania protozoa. In one aspect, the invention isdirected to a method of treating an amoebic infection. In one aspect,the invention is directed to a method of treating a helminth infection.In one aspect, the invention is directed to a method of treating aninfection caused by schistostoma mansoni.

In one aspect, compounds of the invention are administered incombination with one or more additional anti-infective therapeuticagents, such as antibiotics, anti-viral agents, anti-fungal agents,and/or anti-parasitic agents.

The present invention provides a method for inhibiting topoisomerase IIin a subject in need thereof, comprising administering to the subject aneffective amount of a compound according to Formulae (I)-(VI) or acompound shown in Table 1. In one embodiment, topoisomerase II isassociated with a disease, and administering the compound will treat thedisease. In one aspect, the disease is a proliferative disease. Inanother aspect, the proliferative disease is cancer. In one aspect, thedisease is an infection.

The present invention provides a method of treating an inflammatorydisease or disorder in a subject in need thereof, comprisingadministering an effective amount of a compound of Formulae (I)-(VI) ora compound shown in Table 1. In one embodiment, the inflammatory diseaseor disorder is selected from the group consisting of transplantrejection, skin graft rejection, arthritis, rheumatoid arthritis,osteoarthritis, bone diseases associated with increased bone resorption;inflammatory bowel disease, ileitis, ulcerative colitis, Barrett'ssyndrome, Crohn's disease; asthma, adult respiratory distress syndrome,chronic obstructive airway disease; corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis, endophthalmitis;gingivitis, periodontitis; tuberculosis; leprosy; uremic complications,glomerulonephritis, nephrosis; sclerodermatitis, psoriasis, eczema;chronic demyelinating diseases of the nervous system, multiplesclerosis, AIDS-related neurodegeneration, Alzheimer's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis viral, autoimmuneencephalitis; autoimmune disorders, immune-complex vasculitis, systemiclupus erythematosus (SLE); cardiomyopathy, ischemic heart diseasehypercholesterolemia, atherosclerosis, preeclampsia; chronic liverfailure, and brain and spinal cord trauma.

The present invention provides a method of treating an immune disease ordisorder in a subject in need thereof, comprising administering aneffective amount of a compound of Formulae (I)-(VI) or a compound shownin Table 1. In one embodiment, the immune disease or disorder isselected from the group consisting of multiple sclerosis, myastheniagravis, Guillain-Barré, autoimmune uveitis, autoimmune hemolytic anemia,pernicious anemia, autoimmune thrombocytopenia, temporal arteritis,anti-phospholipid syndrome, vasculitides such as Wegener'sgranulomatosis, Behcet's disease, psoriasis, dermatitis herpetiformis,pemphigus vulgaris, vitiligo, Crohn's disease, ulcerative colitis,primary biliary cirrhosis, autoimmune hepatitis, Type 1 orimmune-mediated diabetes mellitus, Grave's disease, Hashimoto'sthyroiditis, autoimmune oophoritis and orchitis, autoimmune disorder ofthe adrenal gland, rheumatoid arthritis, systemic lupus erythematosus,scleroderma, polymyositis, dermatomyositis, ankylosing spondylitis andSjogren's syndrome.

The present invention provides a method of suppressing an immuneresponse in a subject in need thereof, comprising administering aneffective amount of a compound represented by Formulae (I)-(VI) or acompound shown in Table 1. In one embodiment, the subject in need ofimmunosuppression is a subject that has received an organ or tissuetransplant, such as a skin graft, or a heart, kidney, lung, liver,pancreas, cornea, bowel, or stomach transplant, and the like. In anotherembodiment, the subject in need of immunosuppression is a subject thathas received stem cell transplantation. The transplant may be asyngeneic transplant (i.e., from a donor that has the same genetic makeup), an allographic transplant (i.e., from a donor of the same species)or a xenographic transplant (i.e., from a donor that is a differentspecies).

The present invention provides a method of inhibiting the production ofinflammatory cytokines, such as G-CSF, GM-CSF, IL-12, IL-1β, IL-23,IL-6, IL-8, and TNF-α, in a subject in need of such treatment. Themethod comprises administering to the subject an effective amount of acompound represented by Formulae (I)-(VI) or a compound shown in Table1.

1. c-Kit Associated Cancers

SCF binding to c-Kit protects hematopoietic stem and progenitor cellsfrom apoptosis, thereby contributing to colony formation andhematopoiesis. Lee, et al., J. Immunol., (1997) 159:3211-3219.Expression of c-Kit is frequently observed in acute myelocytic leukemia(AML) and is sometimes observed in acute lymphocytic leukemia (ALL). Forreviews, see Sperling, et al., Haemat., (1997) 82:617-621; Escribano, etal., Leuk. Lymph., (1998) 30:459-466. Although c-Kit is expressed in themajority of AML cells, its expression does not appear to be prognosticof disease progression. Sperling, et al, Haemat. (1997) 82:617-621.However, AML cells are protected from apoptosis induced bychemotherapeutic agents when the SCF is bound to c-Kit proteins. Hassan,et al., Acta. Hem., (1996) 95:257-262). Therefore, degradation of c-Kitcaused by the inhibition of Hsp90 by the compounds of the invention willresult in less SCF protected cell, and thus will enhance the efficacy ofchemotherapeutic agents and may induce apoptosis of AML cells.

The clonal growth of cells from patients with myelodysplastic syndrome(Sawada, et al., Blood, (1996) 88:319-327) or chronic myelogenousleukemia (CML) (Sawai, et al., Exp. Hem., (1996) 2:116-122) was found tobe significantly enhanced by SCF in combination with other cytokines.CML is characterized by expansion of Philadelphia chromosome positivecells of the marrow (Verfaillie, et al., Leuk., (1998) 12:136-138),which appears to primarily result from inhibition of apoptotic celldeath (Jones, Curr. Opin. Onc., (1997) 9:3-7). The product of thePhiladelphia chromosome, p210.sup.BCR-ABL, has been reported to mediateinhibition of apoptosis. Bedi, et al., Blood, (1995) 86:1148-1158. Sincep210.sup.BCR-ABL and the c-Kit RTK both inhibit apoptosis, andp62.sup.dok has been suggested as a substrate. Carpino, et al., Cell,(1997) 88:197-204. It is possible that clonal expansion mediated bythese kinases occurs through a common signaling pathway. However, c-Kithas also been reported to interact directly with p210.sup.BCR-ABL whichsuggests that c-Kit may have a more causative role in CML pathology.Hallek, et al., Brit. J. Haem., (1996) 94:5-16. Therefore, degradationof c-Kit caused by the inhibition of Hsp90 by the compounds of theinvention will prove useful in the treatment of CML.

Normal colorectal mucosa does not express c-Kit. Bellone, et al., J.Cell Physiol., (1997) 172:1-11. However, c-Kit is frequently expressedin colorectal carcinoma, and autocrine loops of SCF and c-Kit have beenobserved in several colon carcinoma cell lines. Bellone, et al., J. CellPhysiol., (1997) 172: 1-11; Toyota, et al., Turn. Biol., (1993)14:295-302; Lahm, et al., Cell Growth & Differ., (1995) 6:1111-1118.Furthermore, disruption of the autocrine loop by the use of neutralizingantibodies and downregulation of c-Kit and/or SCF significantly inhibitscell proliferation. Lahm, et al., Cell Growth & Differ., (1995)6:1111-1118; Bellone, et al., J. Cell Physiol., (1997) 172:1-11.

SCF/c-Kit autocrine loops have been observed in gastric carcinoma celllines, and constitutive c-Kit activation also appears to be importantfor gastrointestinal stromal tumors (GISTs). Turner, et al., Blood,(1992) 80:374-381; Hassan, et al., Digest. Dis. Science, (1998) 43:8-14.GISTs are the most common mesenchymal tumor of the digestive system.More than 90% of GISTs express c-Kit, which is consistent with theputative origin of these tumor cells from interstitial cells of Cajal(ICCs). Hirota, et al., Science, (1998) 279:577-580. The c-Kit expressedin GISTs from several different patients was observed to have mutationsin the intracellular juxtamembrane domain leading to constitutiveactivation. Hirota, et al., Science, (1998) 279:577-580. Therefore,degradation of c-Kit caused by the inhibition of Hsp90 by the compoundsof the invention will be an efficacious means for the treatment of thesecancers.

Male germ cell tumors have been histologically categorized intoseminomas which retain germ cell characteristics and nonseminomas whichcan display characteristics of embryonal differentiation. Both seminomasand nonseminomas are thought to arise from a preinvasive stagedesignated carcinoma in situ (CIS). Murty, et al., Sem. Oncol., (1998)25:133-144. Both c-Kit and SCF have been reported to be essential fornormal gonadal development during embryogenesis. Loveland, et al., J.Endocrinol., (1997) 153:337-344. Loss of either the receptor or theligand resulted in animals devoid of germ cells. In postnatal testes,c-Kit has been found to be expressed in Leydig cells and spermatogonia,while SCF was expressed in Sertoli cells. Loveland, et al., J.Endocrinol., (1997) 153:337-344. Testicular tumors develop from Leydigcells with high frequency in transgenic mice expressing human papillomavirus 16 (HPV16) E6 and E7 oncogenes. Kondoh, et al., J. Virol., (1991)65:3335-3339; Kondoh, et al., J. Urol., (1994) 152:2151-2154. Thesetumors express both c-Kit and SCF, and an autocrine loop may contributeto the tumorigenesis associated with the cellular loss of functional p53and the retinoblastoma gene product by association with E6 and E7.Kondoh, et al., Oncogene, (1995) 10:341-347; Dyson, et al., Science,(1989) 243:934-937; Werness, et al., Science, (1990) 248:76-79;Scheffner, et al., Cell, (1990) 63:1129-1136. Defective signalingmutants of SCF or c-Kit inhibited formation of testicular tumors in miceexpressing HPV16 E6 and E7. Kondoh, et al., Oncogene, (1995) 10:341-347;Li, et al., Canc. Res., (1996) 56:4343-4346. Since c-Kit kinaseactivation is pivotal to tumorigenesis in these animals, the compoundsof the invention which inhibit Hsp90, and thereby cause the degradationof c-Kit, will be useful for treating testicular tumors associated withthe human papilloma virus.

Expression of c-Kit in germ cell tumors shows that the receptor isexpressed by the majority of carcinomas in situ and seminomas, but c-Kitis expressed in only a minority of nonseminomas. Strohmeyer, et al.,Canc. Res., (1991) 51:1811-1816; Rajpert-de Meyts, et al., Int. J.Androl., (1994) 17:85-92; Izquierdo, et al., J. Pathol., (1995)177:253-258; Strohmeyer, et al., J. Urol., (1995) 153:511-515;Bokenmeyer, et al., J. Cancer Res. & Clin. Oncol., (1996) 122:301-306;Sandlow, et al., J. Androl., (1996) 17:403-408. Therefore, degradationof c-Kit caused by the inhibition of Hsp90 by the compounds of theinvention will be an efficacious means for the treatment of thesecancers.

SCF and c-Kit are expressed throughout the central nervous system ofdeveloping rodents, and the pattern of expression suggests a role ingrowth, migration and differentiation of neuroectodermal cells. Theexpression of SCF and c-Kit have also been reported in the adult brain.Hamel, et al., J. Neuro-Onc., (1997) 35:327-333). Expression of c-Kithas also been observed in normal human brain tissue. Tada, et al., J.Neuro., (1994) 80:1063-1073). Glioblastoma and astrocytoma, which definethe majority of intracranial tumors, arise from neoplastictransformation of astrocytes. Levin, V. A., et al., Neoplasms of thecentral nervous system, In CANCER: PRINCIPLES AND PRACTICE OF ONCOLOGY(DeVita, V. T., et al., Eds., Philadelphia: Lippincott-Raven (1997))2022-2082. Expression of c-Kit has been observed in glioblastoma celllines and tissues. Berdel, et al., Canc. Res., (1992) 52:3498-3502;Tada, et al., J. Neuro., (1994) 80:1063-1073; Stanulla, et al., Act.Neuropath., (1995) 89:158-165). Therefore, glioblastomas can be treatedby degrading c-Kit. The inhibition of Hsp90 using compounds of theinvention leads to the degredation of c-Kit, and other client proteins.

The association of c-Kit with astrocytoma pathology is less clear.Reports of expression of c-Kit in normal astrocytes have been made.Natali, et al., Int. J. Canc., (1992) 52:197-201; Tada, et al., J.Neuro., (1994) 80:1063-1073. However, others report it is not expressed.Kristt, et al., Neuro., (1993) 33:106-115. In the former case, highlevels of c-Kit expression in high grade tumors were observed, whereasin the latter case researchers were unable to detect any expression inastrocytomas. In addition, contradictory reports of c-Kit and SCFexpression in neuroblastomas also exist. One study found thatneuroblastoma cell lines often express SCF, but rarely express c-Kit. Inprimary tumors, c-Kit was detected in about 8% of neuroblastomas, whileSCF was found in 18% of tumors. Beck, et al., Blood, (1995)86:3132-3138. In contrast, other studies have reported that all 14neuroblastoma cell lines examined contained c-Kit/SCF autocrine loops,and expression of both the receptor and ligand were observed in 45% oftumor samples examined. Cohen, et al., Blood, (1994) 84:3465-3472. Intwo cell lines, anti-c-Kit antibodies inhibited cell proliferation,suggesting that the SCF/c-Kit autocrine loop contributed to growth.Cohen, et al., Blood, (1994) 84:3465-3472. Therefore, degradation ofc-Kit caused by the inhibition of Hsp90 by the compounds of theinvention will be an efficacious means for treating some cancers of thecentral nervous system.

2. BCR-ABL Associated Cancers

The Philadelphia chromosome which generates the fusion protein BCR-ABLis associated with the bulk of chronic myelogenous leukemia (CML)patients (more than 95%), 10-25% of acute lymphocytic leukemia (ALL)patients, and about 2-3% of acute myelogenous leukemias (AML). Inaddition, BCR-ABL is a factor in a variety of other hematologicalmalignancies, including granulocytic hyperplasia resembling CML,myelomonocytic leukemia, lymphomas, and erythroid leukemia. See Lugo, etal., Molecular Cell Bio. (1989), 9:1263-1270; Daley, et al., Science(1990), 247:824-830; Honda, Blood (1998), 91:2067-2075.

A number of different kinds of evidence support the contention thatBCR-ABL oncoproteins, such as p210 and p185 BCR-ABL, are causativefactors in these leukemias. Campbell & Arlinghaus, Current Status of BcrGene Involvement with Human Leukemia, In ADVANCES IN CANCER RESEARCH,(Klein, VandeWoude Eds., Orlando, Fla. Academic Press, Inc., (1991)),57:227-256. The malignant activity is due in large part to the BCR-ABLprotein's highly activated protein tyrosine kinase activity and itsabnormal interaction with protein substrates. Arlinghaus, et al., In:UCLA SYMPOSIA ON MOLECULAR AND CELLULAR BIOLOGY, NEW SERIES, ACUTELYMPHOBLASTIC LEUKEMIA (R. P. Gale & D. Hoelzer, Eds., N.Y.: Alan R.Liss, Inc. (1990)) 108:81-90. The BCR-ABL oncoprotein p210 BCR-ABL isassociated with both CML and ALL, whereas the smaller oncoprotein, p185BCR-ABL, is associated with ALL patients, although some CML patientsalso express p185. Campbell & Arlinghaus, Current Status of Bcr GeneInvolvement with Human Leukemia, In ADVANCES IN CANCER RESEARCH, (Klein,VandeWoude Eds., Orlando, Fla. Academic Press, Inc., (1991)),57:227-256.

3. FLT3 Associated Cancers

FLT3 associated cancers are cancers in which inappropriate FLT3 activityis detected. FLT3 associated cancers include hematologic malignanciessuch as leukemia and lymphoma. In some embodiments of the presentinvention, FLT3 associated cancers include acute myelogenous leukemia(AML), B-precursor cell acute lymphoblastic leukemia, myelodysplasticleukemia, T-cell acute lymphoblastic leukemia, mixed lineage leukemia(MLL) and chronic myelogenous leukemia (CML).

4. EGFR Associated Cancers

EGFR associated cancers are cancers in which inappropriate EGFR activity(e.g., overexpression of EGFR or mutation of EGFR which causesconstitutive tyrosine kinase activity) has been implicated as acontributing factor. Inappropriate EGFR activity has been associatedwith an adverse prognosis in a number of human cancers, such asneuroblastoma; intestinal carcinomas, such as rectum carcinoma, coloncarcinomas, familiary adenomatous polyposis carcinoma and hereditarynon-polyposis colorectal cancer; esophageal carcinoma; labial carcinoma;larynx carcinoma; hypopharynx carcinoma; tongue carcinoma; salivarygland carcinoma; gastric carcinoma; adenocarcinoma; medullary thyroideacarcinoma; papillary thyroidea carcinoma; renal carcinoma; kidneyparenchym carcinoma; ovarian carcinoma; cervix carcinoma; uterine corpuscarcinoma; endometrium carcinoma; chorion carcinoma; pancreaticcarcinoma; prostate carcinoma; testis carcinoma; breast carcinoma;urinary carcinoma; melanoma; brain tumors such as glioblastoma,astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermaltumors; Hodgkin lymphoma; non-Hodgkin lymphoma; Burkitt lymphoma; acutelymphatic leukemia (ALL); chronic lymphatic leukemia (CLL); acutemyeloid leukemia (AML); chronic myeloid leukemia (CML); adult T-cellleukemia lymphoma; hepatocellular carcinoma; gall bladder carcinoma;bronchial carcinoma; small cell lung carcinoma; non-small cell lungcarcinoma; multiple myeloma; basalioma; teratoma; retinoblastoma;choroidea melanoma; seminoma; rhabdomyo sarcoma; craniopharyngeoma;osteosarcoma; chondrosarcoma; myosarcoma; liposarcoma; fibrosarcoma;Ewing sarcoma and plasmocytoma.

In particular, EGFR appears to have an important role in the developmentof human brain tumors. A high incidence of overexpression,amplification, deletion and structural rearrangement of the gene codingfor EGFR has been found in biopsies of brain tumors. In fact, theamplification of the EGFR gene in glioblastoma multiforme tumors is oneof the most consistent genetic alterations known, with EGFR beingoverexpressed in approximately 40% of malignant gliomas and the EGFRvIIImutation being found in about 50% of all glioblastomas. In addition togliomas, abnormal EGFR expression has also been reported in a number ofsquamous epidermoid cancers and breast cancers. Interestingly, evidencealso suggests that many patients with tumors that over-express EGFR havea worse prognosis than those having tumors that do not over-expressEGFR.

Non-small cell lung cancer (NSCLC) includes squamous cell carcinomas,adenocarcinoma, bronchioloalveolar carcinoma (BAC) and large cellundifferentiated carcinoma. A subset of patients with NSCLC have beenshown to have mutations in the tyrosine kinase domain of EGFR which isthought to be necessary for the maintenance of the disease. Treatment ofthis subset of patients with NSCLC with Gefitinib, a tyrosine kinaseinhibitor which targets EGFR, has shown rapid and dramatic clinicalresponse. Consequently, therapeutic strategies that can potentiallyinhibit or reduce the aberrant expression of EGFR are of great interestas potential anti-cancer agents.

5. Combination Therapies and Treatment of Refractory Cancers

The therapeutic agents of the combination therapies of the invention canbe administered sequentially or concurrently. In a specific embodiment,the combination therapies of the invention comprise one or morecompounds of the invention and at least one other therapeutic agentwhich has the same mechanism of action as said compounds. In anotherspecific embodiment, the combination therapies of the invention compriseone or more compounds of the invention and at least one othertherapeutic agent which has a different mechanism of action than saidcompounds. In certain embodiments, the combination therapies of thepresent invention improve the therapeutic effect of one or morecompounds of the invention by functioning together with the additionaltherapeutic agent(s) to produce an additive or synergistic effect. Incertain embodiments, the combination therapies of the present inventionreduce the side effects associated with the additional therapeuticagent(s). In certain embodiments, the combination therapies of thepresent invention reduce the effective dosage of a compound of theinvention and/or an additional therapeutic agent.

The therapeutic agents of the combination therapies can be administeredto a subject, preferably a human subject, in the same pharmaceuticalcomposition. In alternative embodiments, the therapeutic agents of thecombination therapies can be administered concurrently to a subject inseparate pharmaceutical compositions. In another embodiment, thetherapeutic agents may be administered to a subject by the same ordifferent routes of administration.

In a specific embodiment, a pharmaceutical composition comprising one ormore compounds of the invention is administered to a subject, preferablya human, to treat, manage, or ameliorate a proliferative disorder, suchas cancer, or one or more symptom thereof. In accordance with theinvention, pharmaceutical compositions of the invention may alsocomprise one or more additional therapeutic agents which are currentlybeing used, have been used, or are known to be useful in the treatmentof a proliferative disorder, or a symptom thereof.

The invention provides methods for treating a proliferative disorder,such as cancer, or one or more symptoms thereof, in a subject refractory(either completely or partially) to an existing therapeutic agent forthe proliferative disorder The method comprises administering to asubject an effective amount of one or more compounds of the invention inconjunction with an effective amount of one or more additionaltherapeutic agents useful for the treatment of the proliferativedisorder, or a symptom thereof. The invention also provides a method fortreating, a proliferative disorder, or a symptom thereof, byadministering to a subject in need thereof, an effective amount of oneor more compounds of the invention in combination with one or moreadditional therapeutic agent(s) wherein the subject has provenrefractory to said additional therapeutic agent(s).

The compounds of the invention and/or any additional therapeutic agentscan be administered to a subject by any route known to one of skill inthe art. Examples of routes of administration include, but are notlimited to, parenteral, e.g., intravenous, intradermal, subcutaneous,oral (e.g., inhalation), intranasal, transdermal (topical), transmucosaland rectal administration.

6. Agents Useful in Combination with the Compounds of the Invention

Without being bound by any particular theory, it is believed that thecompounds of the invention can be particularly effective at treatingsubjects whose cancer has become drug resistant or multi-drug resistant.Although currently available chemotherapeutic agents may initially causetumor regression, most agents that are currently used to treat cancertarget only one pathway to tumor progression. Therefore, in manyinstances, after treatment with one or more chemotherapeutic agents, thetumor may become resistant to said one or more agents, and no longerresponds positively to treatment. One of the advantages of inhibitingHsp90 activity is that several of its client proteins, which are mostlyprotein kinases or transcription factors involved in signaltransduction, have been shown to be involved in the progression ofcancer. Thus, inhibition of Hsp90 provides a method of short circuitingseveral pathways for tumor progression simultaneously. Therefore, it isbelieved that treatment of cancer with an Hsp90 inhibitor of theinvention either alone, or in combination with additional therapeuticagents, is more likely to result in regression or elimination of thetumor, and less likely to result in the development of more aggressivemultidrug resistant tumors than other currently available therapies.

In one embodiment, one or more compounds of the invention can beadministered with additional thereapeutic agents that are tyrosinekinase inhibitors (e.g., Gefitinib or Erlotinib, which inhibit EGFRtyrosine kinase activity). In another embodiment, the compounds of theinvention can be administered to a subject whose cancer has becomeresistant to a tyrosine kinase inhibitor (e.g., Gefitinib or Erlotinib).In this embodiment, the compounds of the invention can be administeredeither alone or in combination with the tyrosine kinase inhibitor.

In another embodiment, the compounds of the invention are useful fortreating a subject with a hematological cancer that have becomeresistant to Imatinib, a chemotherapeutic agent that acts by inhibitingtyrosine kinase activity of BCR-ABL. In patients with CML in the chronicphase, as well as in a blast crisis, treatment with Imatinib typicallywill induce remission. However, in many cases, particularly in thosesubjects who were in a blast crisis before remission, the remission isnot durable because the BCR-ABL fusion protein develops mutations in thetyrosine kinase domain that cause it to be resistance to Imatinib.Nimmanapalli, et al., Cancer Research (2001), 61:1799-1804; Gorre, etal., Blood (2002), 100:3041-3044. Compounds of the invention act byinhibiting the activity of Hsp90, which disrupts BCR-ABL/Hsp90complexes. When BCR-ABL is not complexed to Hsp90, it is rapidlydegraded. Therefore, compounds of the invention are effective intreating Imatinib resistant cancers since they act through a differentmechanism than Imatinib. One or more compound(s) of the invention can beadministered alone or with Imatinib to a subject that has a BCR-ABLassociated cancer that is not resistant to Imatinib, or to a subjectwhose cancer has become resistant to Imatinib.

Anti-cancer agents that can be co-administered with the compounds of theinvention include Taxol™, also referred to as “paclitaxel”, and analogsof Taxol™, such as Taxotere™. Paclitaxel is a well-known anti-cancerdrug which acts by enhancing and stabilizing microtubule formation.Compounds that have the basic taxane skeleton as a common structuralfeature have also been shown to have the ability to arrest cells in theG2-M phases due to the stabilization or inhibition of microtubules.

Other anti-cancer agents that can be employed in combination with thecompounds of the invention include: Avastin; Adriamycin; Dactinomycin;Bleomycin; Vinblastine; Cisplatin; acivicin; aclarubicin; acodazolehydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;interleukin II (including recombinant interleukin II, or rIL2);interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3;interferon β-I a; interferon γ-I b; iproplatin; irinotecanhydrochloride; lanreotide acetate; letrozole; leuprolide acetate;liarozole hydrochloride; lometrexol sodium; lomustine; losoxantronehydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride;megestrol acetate; melengestrol acetate; melphalan; menogaril;mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide;safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other anti-cancer drugs that can be employed in combination with thecompounds of the invention include: 20-epi-1,25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;aldesleukin; ALL-TK antagonists; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; BCR/ABLantagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bisantrene; bisaziridinylspermine; bisnafide; bistratene A;breflate; budotitane; buthionine sulfoximine; calcipotriol; calphostinC; camptothecin derivatives; canarypox IL-2; capecitabine;carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700;cartilage derived inhibitor; carzelesin; casein kinase inhibitors(ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; clomifeneanalogues; clotrimazole; collismycin A; collismycin B; combretastatinA4; combretastatin analogue; conagenin; crambescidin 816; crisnatol;cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; didemnin B;didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; docosanol; dolasetron; doxifluridine; dronabinol;duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;eflornithine; elemene; emitefur; epirubicin; epristeride; estramustineanalogue; estrogen agonists; estrogen antagonists; exemestane;fadrozole; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; glutathioneinhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;ibandronic acid; idarubicin; idoxifene; idramantone; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; leukemiainhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; maspin; matrilysin inhibitors;matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustardanti-cancer agent; mycaperoxide B; mycobacterial cell wall extract;myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin;nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim;nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase;nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides;onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perillyl alcohol; phenazinomycin; phenylacetate; phosphataseinhibitors; picibanil; pilocarpine hydrochloride; pirarubicin;piritrexim; placetin A; placetin B; plasminogen activator inhibitor;platinum complex; platinum compounds; platinum-triamine complex;prednisone; propyl bisacridone; prostaglandin J2; proteasome inhibitors;protein A-based immune modulator; protein kinase C inhibitor; proteinkinase C inhibitors, microalgal; protein tyrosine phosphataseinhibitors; purine nucleoside phosphorylase inhibitors; purpurins;pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate;raf antagonists; raltitrexed; ramosetron; ras farnesyl proteintransferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptinedemethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RIIretinamide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; signal transduction modulators; single chainantigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; splenopentin; spongistatin 1; squalamine;stem cell inhibitor; stem-cell division inhibitors; stipiamide;stromelysin inhibitors; sulfinosine; superactive vasoactive intestinalpeptide antagonist; suradista; suramin; swainsonine; syntheticglycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine;tazarotene; tellurapyrylium; telomerase inhibitors; temozolomide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; titanocene bichloride; topsentin; toremifene; totipotentstem cell factor; translation inhibitors; tretinoin; triacetyluridine;triciribine; tropisetron; turosteride; tyrosine kinase inhibitors;tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growthinhibitory factor; urokinase receptor antagonists; variolin B; vectorsystem, erythrocyte gene therapy; velaresol; veramine; verdins;vinxaltine; vitaxin; zanoterone; zilascorb and zinostatin stimalamer.Preferred anti-cancer drugs are 5-fluorouracil and leucovorin.

Other chemotherapeutic agents that can be employed in combination withthe compounds of the invention include but are not limited to alkylatingagents, antimetabolites, natural products or hormones. Examples ofalkylating agents useful for the treatment of T-cell malignancies in themethods and compositions of the invention include, but are not limitedto, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas(e.g., carmustine, lomusitne, etc.) and triazenes (e.g., decarbazine,etc.). Examples of antimetabolites useful for the treatment of T-cellmalignancies in the methods and compositions of the invention include,but are not limited to, folic acid analogs (e.g., methotrexate),pyrimidine analogs (e.g., Cytarabine) and purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin). Examples of natural productsuseful for the treatment of T-cell malignancies in the methods andcompositions of the invention include, but are not limited to, vincaalkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g.,etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin),enzymes (e.g., L-asparaginase) and biological response modifiers (e.g.,interferon alpha).

Examples of alkylating agents that can be employed in combination withthe compounds of the invention include, but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.) and triazenes (e.g., decarbazine, etc.). Examples ofantimetabolites useful for the treatment of cancer in the methods andcompositions of the invention include, but are not limited to, folicacid analogs (e.g., methotrexate), pyrimidine analogs (e.g.,fluorouracil, floxouridine, Cytarabine) and purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin). Examples of natural productsuseful for the treatment of cancer in the methods and compositions ofthe invention include, but are not limited to, vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide,teniposide), antibiotics (e.g., actinomycin D, daunorubicin,doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g.,L-asparaginase) and biological response modifiers (e.g., interferon α).Examples of hormones and antagonists useful for the treatment of cancerin the methods and compositions of the invention include, but are notlimited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide) andgonadotropin releasing hormone analog (e.g., leuprolide). Other agentsthat can be used in the methods and compositions of the invention forthe treatment of cancer include platinum coordination complexes (e.g.,cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone),substituted ureas (e.g., hydroxyurea), methyl hydrazine derivatives(e.g., procarbazine) and adrenocortical suppressants (e.g., mitotane,aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilization or inhibition of microtubules, and which canbe used in combination with the compounds of the invention include,without limitation, the following marketed drugs and drugs indevelopment: Erbulozole (also known as R-55104), Dolastatin 10 (alsoknown as DLS-10 and NSC-376128), Mivobulin isethionate (also known asCI-980), Vincristine, NSC-639829, Discodermolide (also known asNVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins(such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such asSpongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 andSpongistatin 9), Cemadotin hydrochloride (also known as LU-103793 andNSC-D-669356), Epothilones (such as Epothilone A, Epothilone B,Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D(also referred to as KOS-862, dEpoB, and desoxyepothilone B), EpothiloneE, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide,16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705),21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF) and26-fluoroepothilone), Auristatin PE (also known as NSC-654663),Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known asLS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477(Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristinesulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known asWS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy ofSciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651),SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97(Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko),IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739(Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto,also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A),Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known asNSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 andTI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 andWHI-261), H10 (Kansas State University), H16 (Kansas State University),Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker HughesInstitute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute),SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(Wyeth, also known as SPA-110, trifluoroacetate salt), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-0Y-007 (National Health Research Institutes) and SSR-250411(Sanofi).

7. Anti-Infective Agents Useful in Combination with the Compounds of theInvention

In one embodiment relating to infections, the other therapeutic agentmay be an anti-infective agent. In one embodiment, an anti-infectiveagent is selected from an anti-fungal, anti-bacterial, anti-viral oranti-parasitic agent.

Anti-fungal agents that can be co-administered with the compounds of theinvention include, but are not limited to, polyene antifungals (e.g.,amphotericin and nystatin), azole antifungals (e.g., ketoconazole,miconazole, fluconazole, itraconazole, posaconazole, ravuconazole,voriconazole, clotrimazole, econazole, oxiconazole, sulconazole,terconazole, butoconazole, and tioconazole), amorolfine, butenafine,naftifine, terbinafine, flucytosine, nikkomycin Z, caspofungin,micafungin (FK463), anidulafungin (LY303366), griseofulvin,ciclopiroxolamine, tolnaftate, intrathecal, haloprogrin andundecylenate.

Anti-bacterial agents that can be co-administered with the compounds ofthe invention include, but are not limited to, sulfa drugs (e.g.,sulfanilamide), folic acid analogs (e.g., trimethoprim), beta-lactams(e.g., penacillin, cephalosporins), aminoglycosides (e.g., stretomycin,kanamycin, neomycin, gentamycin), tetracyclines (e.g.,chlorotetracycline, oxytetracycline and doxycycline), macrolides (e.g.,erythromycin, azithromycin and clarithromycin), lincosamides (e.g.,clindamycin), streptogramins (e.g., quinupristin and dalfopristin),fluoroquinolones (e.g., ciprofloxacin, levofloxacin and moxifloxacin),polypeptides (e.g., polymixins), rifampin, mupirocin, cycloserine,aminocyclitol (e.g., spectinomycin), glycopeptides (e.g., vancomycin),oxazolidinones (e.g., linezolid), ribosomes, chloramphenicol, fusidicacid and metronidazole.

Anti-viral agents that can be co-administered with the compounds of theinvention include, but are not limited to, Emtricitabine (FTC);Lamivudine (3TC); Carbovir; Acyclovir; Interferon; Famciclovir;Penciclovir; Zidovudine (AZT); Didanosine (ddI); Zalcitabine (ddC);Stavudine (d4T); Tenofovir DF (Viread); Abacavir (ABC); L-(−)-FMAU;L-DDA phosphate prodrugs; β-D-dioxolane nucleosides such asβ-D-dioxolanyl-guanine (DG), β-D-dioxolanyl-2,6-diaminopurine (DAPD) andβ-D-dioxolanyl-6-chloropurine (ACP); non-nucleoside RT inhibitors suchas Nevirapine (Viramune), MKC-442, Efavirenz (Sustiva), Delavirdine(Rescriptor); protease inhibitors such as Amprenavir, Atazanavir,Fosamprenavir, Indinavir, Kaletra, Nelfinavir, Ritonavir, Saquinavir,AZT, DMP-450; combination treatments such as Epzicom (ABC+3TC), Trizivir(ABC+3TC+AZT) and Truvada (FTC+Viread); Omega IFN (BioMedicines Inc.);BILN-2061 (Boehringer Ingelheim); Summetrel (Endo Pharmaceuticals);Roferon A (F. Hoffman-La Roche); Pegasys (F. Hoffman-La Roche);Pegasys/Ribaravin (F. Hoffman-La Roche); CellCept (F. Hoffman-La Roche);Wellferon (GlaxoSmithKline); Albuferon-α (Human Genome Sciences);Levovirin (ICN Pharmaceuticals); IDN-6556 (Idun Pharmaceuticals); IP-501(Indevus Pharmaceuticals); Actimmune (InterMune); Infergen A(InterMune); ISIS 14803 (ISIS Pharmaceuticals); JTK-003 (Japan Tobacco);Pegasys/Ceplene (Maxim Pharmaceuticals); Ceplene (MaximPharmaceuticals); Civacir (Nabi Biopharmaceuticals); Intron A/Zadaxin(RegeneRx); Levovirin (Ribapharm); Viramidine (Ribapharm); Heptazyme(Ribozyme Pharmaceuticals); Intron A (Schering-Plough); PEG-Intron(Schering-Plough); Rebetron (Schering-Plough); Ribavirin(Schering-Plough); PEG-Intron/Ribavirin (Schering-Plough); Zadazim(SciClone); Rebif (Serono); IFN-β/EMZ701 (Transition Therapeutics); T67(Tularik Inc.); VX-497 (Vertex Pharmaceuticals); VX-950/LY-570310(Vertex Pharmaceuticals); Omniferon (Viragen); XTL-002 (XTLBiopharmaceuticals); SCH 503034 (Schering-Plough); isatoribine and itsprodrugs ANA971 and ANA975 (Anadys); R1479 (Roche Biosciences);Valopicitabine (Idenix); NIM811 (Novartis); Actilon (ColeyPharmaceuticals); Pradefovir (Metabasis Therapeutics); zanamivir;adefovir, adefovir dipivoxil, oseltamivir; vidarabine; gancyclovir;valganciclovir; amantadine; rimantadine; relenza; tamiflu; amantadine;entecavir and pleconaril.

Anti-parasitic agents that can be co-administered with the compounds ofthe invention include, but are not limited to, avermectins, milbemycins,lufenuron, imidacloprid, organophosphates, pyrethroids, sufanamides,iodquinol, diloxanide furoate, metronidazole, paromycin, azithromycin,quinacrine, furazolidone, tinidazole, ornidazole, bovine colostrum,bovine dialyzable leukocyte extract, chloroquine, chloroquine phosphate,diclazuril, eflornithine, paromomycin, pentamidine, pyrimethamine,spiramycin, trimethoprim-sulfamethoxazole, albendazole, quinine,quinidine, tetracycline, pyrimethamine-sulfadoxine, mefloquine,doxycycline, proguanil, clindamycin, suramin, melarsoprol, diminazene,nifurtimox, spiroarsoranes, ketoconazole, terbinafine, lovastatin,sodium stibobgluconate, N-methylglucamine antimonate, amphotericin B,allopurinol, itraconazole, sulfadiazine, dapsone, trimetrexate,clarithromycin, roxithromycin, atovaquone, aprinocid, tinidazole,mepacrine hydrochloride, emetine, polyaminopropyl biguanide,paromomycin, benzimidazole, praziquantel and albendazole.

8. Steroid or Non-Steroidal Anti-Inflammatory Agents Useful inCombination with the Compounds of the Invention

In one embodiment, relating to autoimmune, allergic and inflammatoryconditions, the one or more additional therapeutic agent(s) may be asteroid or a non-steroidal anti-inflammatory agent. Particularly usefulnon-steroidal anti-inflammatory agents include, but are not limited to,aspirin; ibuprofen; diclofenac; naproxen; benoxaprofen; flurbiprofen;fenoprofen; flubufen; ketoprofen; indoprofen; piroprofen; carprofen;oxaprozin; pramoprofen; muroprofen; trioxaprofen; suprofen; aminoprofen;tiaprofenic acid; fluprofen; bucloxic acid; indomethacin; sulindac;tolmetin; zomepirac; tiopinac; zidometacin; acemetacin; fentiazac;clidanac; oxpinac; mefenamic acid; meclofenamic acid; flufenamic acid;niflumic acid; tolfenamic acid; diflurisal; flufenisal; salicylic acidderivatives, including aspirin, sodium salicylate, choline magnesiumtrisalicylate, salsalate, diflunisal, salicylsalicylic acid,sulfasalazine and olsalazin; para-aminophennol derivatives includingacetaminophen and phenacetin; indole and indene acetic acids includingindomethacin, sulindac and etodolac; heteroaryl acetic acids includingtolmetin, diclofenac and ketorolac; anthranilic acids (fenamates)including mefenamic acid and meclofenamic acid; enolic acids includingoxicams (piroxicam, sudoxicam, isoxicam and tenoxicam);pyrazolidinediones (phenylbutazone, oxyphenthartazone); and alkanones,including nabumetone; and pharmaceutically acceptable salts thereof andmixtures thereof. For a more detailed description of the NSAIDs, seePaul A. Insel, Analgesic-Antipyretic and Antiinflammatory Agents andDrugs Employed in the Treatment of Gout, In GOODMAN & GILMAN'S THEPHARMACOLOGICAL BASIS OF THERAPEUTICS (P. B. Molinhoff & R. W. RuddonEds., 9^(th) ed (1996)) 617-57; 2 GLEN R. HANSON, ANALGESIC, ANTIPYRETICAND ANTI-INFLAMMATORY DRUGS IN REMINGTON: THE SCIENCE AND PRACTICE OFPHARMACY (A. R. Gennaro Ed., 19th ed. (1995)) 1196-1221.

Of particular relevance to allergic disorders, the additionaltherapeutic agent used in combination with a compound of the inventionmay be an antihistamine. Useful antihistamines include, but are notlimited to, loratadine, cetirizine, fexofenadine, desloratadine,diphenhydramine, chlorpheniramine, chlorcyclizine, pyrilamine,promethazine, terfenadine, doxepin, carbinoxamine, clemastine,tripelennamine, brompheniramine, hydroxyzine, cyclizine, meclizine,cyproheptadine, phenindamine, acrivastine, azelastine, levocabastine andmixtures thereof. For a more detailed description of antihistamines, seeGOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (10^(th)ed. (2001)) 651-57.

Immunosuppressive agents include glucocorticoids, corticosteroids, suchas Prednisone or Solumedrol; T cell blockers, such as cyclosporin A andFK506; purine analogs, such as azathioprine (Imuran); pyrimidineanalogs, such as cytosine arabinoside; alkylating agents, such asnitrogen mustard, phenylalanine mustard, buslfan and cyclophosphamide;folic acid analogs, such as aminopterin and methotrexate; antibiotics,such as rapamycin, actinomycin D, mitomycin C, puramycin, andchloramphenicol; human IgG; antilymphocyte globulin (ALG); andantibodies, such as anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5,anti-CD7, anti-IL-2 receptor, anti-alpha/beta TCR, anti-ICAM-1,anti-CD20 (Rituxan), anti-IL-12 and antibodies to immunotoxins.

E. Compositions and Methods for Administering Therapies

The present invention provides compositions for the treatment ofproliferative disorders, such as cancer. In a specific embodiment, acomposition comprises one or more compounds of the invention, or apharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrugthereof. In another embodiment, a composition of the invention comprisesone or more therapeutic agents in addition to a compound of theinvention, or a pharmaceutically acceptable salt, solvate, clathrate,hydrate, or prodrug thereof. In another embodiment, a composition of theinvention comprises one or more compounds of the invention, or apharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrugthereof, and one or more additional therapeutic agents. In anotherembodiment, the composition comprises a compound of the invention, or apharmaceutically acceptable salt, solvate, clathrate, hydrate, orprodrug thereof, and a pharmaceutically acceptable carrier, diluent orexcipient.

In a preferred embodiment, a composition of the invention is apharmaceutical composition in a single unit dosage form. Pharmaceuticalcompositions and dosage forms of the invention comprise one or moreactive ingredients in relative amounts and are formulated in such a waythat a given pharmaceutical composition or dosage form can be used totreat or prevent proliferative disorders, such as cancer. Preferredpharmaceutical compositions and dosage forms comprise a compound ofFormulae (I)-(VI) or a compound in Table 1, optionally in combinationwith one or more additional therapeutic agents. In one embodiment, thepharmaceutical composition includes one or more additional therapeuticagent, such as one or more additional anti-inflammatory agent or one ormore immunosuppressant.

The pharmaceutical compositions can be used in therapy, e.g., to treat amammal with an infection. In one embodiment, the pharmaceuticalcomposition includes one or more additional therapeutic agents, such asone or more additional anti-infective agent(s).

In another embodiment, the present invention is the use of a compound ofany one of Formulae (I)-(VI), or a compound in Table 1, disclosed hereinfor the manufacture of a medicament for treating a mammal with aninfection.

In another embodiment, the present invention is the use of a compound ofany one of Formulae (I)-(VI), or a compound in Table 1, disclosed hereinfor the manufacture of a medicament for treatment of a mammal with aninflammatory or autoimmune disorder or for treatment of a mammal in needof immunosuppression.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, oral (e.g., inhalation),intranasal, transdermal (topical), transmucosal, and rectaladministration. In a specific embodiment, the composition is formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for intravenous, subcutaneous, intramuscular, oral, intranasalor topical administration to human beings. In a preferred embodiment, apharmaceutical composition is formulated in accordance with routineprocedures for subcutaneous administration to human beings.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES(18th ed., Mack Publishing, Easton Pa. (1990)).

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art, including, but notlimited to, the way in which the dosage form will be administered to apatient. For example, oral dosage forms such as tablets may containexcipients not suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines (e.g., N-desmethylvenlafaxineand N,N-didesmethylvenlafaxine) are particularly susceptible to suchaccelerated decomposition. Consequently, this invention encompassespharmaceutical compositions and dosage forms that contain little, ifany, lactose. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient. Lactose-freecompositions of the invention can comprise excipients that are wellknown in the art and are listed, for example, in the U.S. PHARMOCOPIA(USP) SP (XXI)/NF (XVI). In general, lactose-free compositions compriseactive ingredients, a binder/filler and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. Preferredlactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand anhydrous dosage forms, since water can facilitate the degradationof some compounds. For example, the addition of water (e.g., 5%) iswidely accepted in the pharmaceutical arts as a means of simulatinglong-term storage in order to determine characteristics such asshelf-life or the stability of formulations over time. See, e.g., JENST. CARSTENSEN, DRUG STABILITY: PRINCIPLES & PRACTICE (2d. ed. (1995))379-80. In effect, water and heat accelerate the decomposition of somecompounds. Anhydrous pharmaceutical compositions and dosage forms of theinvention can be prepared using anhydrous or low moisture containingingredients and low moisture or low humidity conditions. Pharmaceuticalcompositions and dosage forms that comprise lactose and at least oneactive ingredient that has a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers or salt buffers.

1) Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed., MackPublishing, Easton, Pa. (1990)).

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation, ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing the active ingredientsin a free-flowing form such as powder or granules, optionally mixed withan excipient, in a suitable machine. Molded tablets can be made bymolding a mixture of the powdered active ingredient moistened with aninert liquid diluent in a suitable machine.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants and lubricants. Binders suitable for use in pharmaceuticalcompositions and dosage forms include, but are not limited to, cornstarch, potato starch or other starches, gelatin, natural and syntheticgums such as acacia, sodium alginate, alginic acid, other alginates,powdered tragacanth, guar gum, cellulose and its derivatives (e.g.,ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium,sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methylcellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,microcrystalline cellulose and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, Marcus Hook,Pa.), and mixtures thereof. One specific binder is a mixture ofmicrocrystalline cellulose and sodium carboxymethyl cellulose sold asAVICEL RC-581. Suitable anhydrous or low moisture excipients oradditives include AVICEL-PH-103J and Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch and mixtures thereof. Thebinder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants can be used in the pharmaceutical compositions of theinvention to provide tablets that disintegrate when exposed to anaqueous environment. Tablets that contain too much disintegrant maydisintegrate in storage, while those that contain too little may notdisintegrate at a desired rate or under the desired conditions. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art.Typical pharmaceutical compositions comprise from about 0.5 to about 15weight percent of disintegrant, preferably from about 1 to about 5weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, other algins, calcium carbonate, microcrystallinecellulose, croscarmellose sodium, other celluloses, crospovidone,polacrilin potassium, sodium starch glycolate, pre-gelatinized starch,potato or tapioca starch, other starches, clays, gums and mixturesthereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oiland/or soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agarand mixtures thereof. Additional lubricants include, for example, asyloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co.,Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed byDegussa Co., Plano, Tex.), CAB-O-SIL (sold by Cabot Co., Boston, Mass.)and mixtures thereof. If used at all, lubricants are typically used inan amount of less than about 1 weight percent of the pharmaceuticalcompositions or dosage forms into which they are incorporated.

2) Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556 and 5,733,566. Such dosage forms can beused to provide slow or controlled-release of one or more activeingredients using, for example, hydropropylmethyl cellulose, polymermatrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres or a combinationthereof. Suitable controlled-release formulations known to those ofordinary skill in the art, including those described herein, can bereadily selected for use with the active ingredients of the invention.The invention thus encompasses single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules,gelcaps and caplets that are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency and increased patient compliance.

Most controlled-release formulations are designed to initially releasean initial amount of a drug (active ingredient) that produces thedesired therapeutic effect, and thereafter gradually and continuallyrelease of other amounts of the drug to maintain this level oftherapeutic effect over an extended period of time. In order to maintaina relatively consistent level of drug in the body, the drug must bereleased at a rate similar to the rate at which the drug is metabolizedand excreted from the body. Controlled-release of an active ingredientcan be stimulated by various conditions including, but not limited to,pH, temperature, enzymes, water, or other physiological conditions orcompounds.

3) Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular and intraarterial. Becauseparental administration typically bypasses a patient's natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: water for injection USP; aqueousvehicles such as, but not limited to, sodium chloride injection,Ringer's injection, dextrose injection, dextrose and sodium chlorideinjection, and lactated Ringer's injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

4) Transdermal Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., REMINGTON'SPHARMACEUTICAL SCIENCES (16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990)) and INTRODUCTION TO PHARMACEUTICAL DOSAGE FORMS (4th ed.,Lea & Febiger, Philadelphia (1985)). Dosage forms suitable for treatingmucosal tissues within the oral cavity can be formulated as mouthwashesor as oral gels. Further, transdermal dosage forms include “reservoirtype” or “matrix type” patches, which can be applied to the skin andworn for a specific period of time to permit the penetration of adesired amount of active ingredient(s).

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oiland mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., REMINGTON'SPHARMACEUTICAL SCIENCES (16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990)).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredient(s) of the invention. For example, penetrationenhancers can be used to assist in delivery of the active ingredient(s)to the tissue. Suitable penetration enhancers include, but are notlimited to: acetone; various alcohols such as ethanol, oleyl andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

5) Dosage & Frequency of Administration

The amount of the compound or pharmaceutical composition of theinvention which will be effective in the treatment of a disease ordisorder, e.g. a proliferative disorder, such as cancer, or one or moresymptoms thereof, will depend on the nature and severity of the diseaseand the route by which the active ingredient is administered. Thefrequency and dosage will also vary according to factors specific foreach patient depending on the specific therapy (e.g., therapeutic agent)administered, the severity of the disorder or disease, the route ofadministration, and the age, body, weight, response and the past medicalhistory of the patient. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.Suitable regiments can be selected by one skilled in the art byconsidering such factors and by following, for example, dosages reportedin the literature and recommended in the PHYSICIAN'S DESK REFERENCE(57th ed., 2003).

Exemplary doses of a small molecule include milligram or microgramamounts of the small molecule per kilogram of subject or sample weight(e.g., about 1 mg/kg to about 500 mg/kg, about 0.1 mg/kg to about 5mg/kg, or about 0.001 mg/kg to about 0.05 mg/kg).

In general, the recommended daily dose range of a compound of theinvention for the conditions described herein lies within the range offrom about 0.01 mg to about 1000 mg per day, given as a single,once-a-day dose preferably as divided doses throughout a day. In oneembodiment, the daily dose is administered twice daily in equallydivided doses. Specifically, a daily dose range should be from about 5mg to about 500 mg per day, more specifically, between about 10 mg andabout 200 mg per day. In managing the patient, the therapy should beinitiated at a lower dose, perhaps about 1 mg to about 25 mg, andincreased if necessary up to about 200 mg to about 1000 mg per day aseither a single dose or divided doses, depending on the patient's globalresponse. It may be necessary to use dosages of the active ingredientoutside the ranges disclosed herein in some cases, as will be apparentto those of ordinary skill in the art. Furthermore, it is noted that theclinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse.

Different therapeutically effective amounts may be applicable fordifferent disease or disorder, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such a disease or disorder, e.g.proliferative disorders, but insufficient to cause, or sufficient toreduce, adverse effects associated with the compounds of the inventionare also encompassed by the above described dosage amounts and dosefrequency schedules. Further, when a patient is administered multipledosages of a compound of the invention, not all of the dosages need bethe same. For example, the dosage administered to the patient may beincreased to improve the prophylactic or therapeutic effect of thecompound or it may be decreased to reduce one or more side effects thata particular patient is experiencing.

In a specific embodiment, the dosage of the composition of the inventionor a compound of the invention administered to prevent, treat, manage,or ameliorate a disorders, such as cancer, or one or more symptomsthereof in a patient is 150 μg/kg, preferably 250 μg/kg, 500 μg/kg, 1mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's body weight. Inanother embodiment, the dosage of the composition of the invention or acompound of the invention administered to prevent, treat, manage, orameliorate a proliferative disorders, such as cancer, or one or moresymptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mgto 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7 mg, 0.25 mg to 5 mg,0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

The dosages of prophylactic or therapeutic agents other than compoundsof the invention, which have been or are currently being used toprevent, treat, manage, or ameliorate diseases or disorders, e.g.proliferative disorders, such as cancer, or one or more symptoms thereofcan be used in the combination therapies of the invention. Preferably,dosages lower than those which have been or are currently being used toprevent, treat, manage, or ameliorate a disease or disorder, e.g.proliferative disorders, or one or more symptoms thereof, are used inthe combination therapies of the invention. The recommended dosages ofagents currently used for the prevention, treatment, management, oramelioration of a disease or disorder, e.g. proliferative disorders,such as cancer, or one or more symptoms thereof, can obtained from anyreference in the art including, but not limited to, Hardman et al.,eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis OfTherapeutics 9^(th) Ed, Mc-Graw-Hill, New York; Physician's DeskReference (PDR) 57^(th) Ed., 2003, Medical Economics Co., Inc.,Montvale, N.J., which are incorporated herein by reference in itsentirety.

In certain embodiments, when the compounds of the invention areadministered in combination with another therapy, the therapies areadministered less than 5 minutes apart, less than 30 minutes apart, 1hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, atabout 2 hours to about 3 hours apart, at about 3 hours to about 4 hoursapart, at about 4 hours to about 5 hours apart, at about 5 hours toabout 6 hours apart, at about 6 hours to about 7 hours apart, at about 7hours to about 8 hours apart, at about 8 hours to about 9 hours apart,at about 9 hours to about 10 hours apart, at about 10 hours to about 11hours apart, at about 11 hours to about 12 hours apart, at about 12hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part.In one embodiment, two or more therapies are administered within thesame patent visit.

In certain embodiments, one or more compounds of the invention and oneor more other the therapies are cyclically administered. Cycling therapyinvolves the administration of a first therapy for a period of time,followed by the administration of a second therapy for a period of time,followed by the administration of a third therapy for a period of timeand so forth, and repeating this sequential administration, i.e., thecycle in order to reduce the development of resistance to one of theagents, to avoid or reduce the side effects of one of the agents, and/orto improve the efficacy of the treatment.

In certain embodiments, administration of the same compound of theinvention may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating proliferative disorders, such ascancer, or one or more symptoms thereof, said methods comprisingadministering to a subject in need thereof a dose of at least 150 μg/kg,preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, atleast 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg,at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150mg/kg, or at least 200 mg/kg or more of one or more compounds of theinvention once every day, preferably, once every 2 days, once every 3days, once every 4 days, once every 5 days, once every 6 days, onceevery 7 days, once every 8 days, once every 10 days, once every twoweeks, once every three weeks, or once a month.

F. Other Embodiments

The compounds of the invention may be used as research tools (forexample, to evaluate the mechanism of action of new drug agents, toisolate new drug discovery targets using affinity chromatography, asantigens in an ELISA or ELISA-like assay, or as standards in in vitro orin vivo assays). These and other uses and embodiments of the compoundsand compositions of this invention will be apparent to those of ordinaryskill in the art.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds of the invention. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe purpose and interest of this invention. The following examples areset forth to assist in understanding the invention and should not beconstrued as specifically limiting the invention described and claimedherein. Such variations of the invention, including the substitution ofall equivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulation or minorchanges in experimental design, are to be considered to fall within thescope of the invention incorporated herein.

EXAMPLES Example 1 Synthesis of Compound 1

Step-1:

To a stirred suspension of 0.20 g (0.53 mmols) of resorcinol boronicacid 1, 0.18 g (0.53 mmols) of bromopyrrole derivative 2, and 0.43 g(1.32 mmols) of CS₂CO₃ in 10 mL of dioxane in a round bottomed flask,was added 30 mg (53 μmols) of Pd₂(dba)₃ followed by 28 mg (0.106 mmols)of triphenylphosphine and the flask was thoroughly purged with argon.The mixture was then heated at 100° C. overnight and concentrated. Waterwork up using ethyl acetate to extract the product followed bychromatography afforded 0.28 g of the pure product 3.

Step-2:

a) Hydrolysis: A mixture of 0.28 g (0.47 mmols) of 3 and 100 mg (2.37mmols) of LiOH was refluxed in the solvent mixture 5:5:3 (THF:MeOH:H₂O,13 mL) overnight and concentrated. The resultant aqueous mixture wasacidified using 2M HCl till pH equalled 4 and the product was extractedwith ethyl acetate to afford 0.25 g of the hydrolyzed product.

b) Amide formation: To a mixture of 0.25 g (0.44 mmols) of the abovehydrolyzed product, 40 mg (0.89 mmols) of ethylamine (2.0M solution inTHF) in 15 mL of dichloromethane was added, followed by 0.13 g (0.66mmols) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochlorideand 5 mg of 4-dimethylaminopyridine. The mixture was stirred at roomtemperature for 2 h. The mixture was then filter through a short pad ofsilica gel, eluted with 3:1 hexane:ethyl acetate mixture andconcentrated to obtain 0.21 g of the product 4 as colorless oil.

Step-3:

A mixture of 0.21 g (0.35 mmols) of 4 was hydrogenated using 40 mg of10% Pd—C in 20 mL of MeOH using balloon as the source of hydrogen. Thereaction was complete in 2 h at room temperature. The mixture was thenfilter through celite and concentrated. Filtering the product through ashort pad of silica gel, eluting with 1:1 hexane:ethyl acetate andconcentration of the filtrate afforded 0.12 g of the pure product 5 ascolorless foam.

¹H-NMR (CDCl₃, 300 MHz): δ 6.79-6.62 (m, 5H), 6.35 (s, 1H), 6.16-6.15(m, 1H), 5.93 (bs, 1H), 5.65 (bs, 1H), 5.40 (s, 1H), 5.29 (s, 1H), 3.70(s, 3H), 3.38 (quintet, J=5.4 Hz, 2H), 3.08 (septet., J=5.1 Hz, 1H),1.16 (t, J=5.4 Hz, 3H), 1.08 (d, J=5.1 Hz, 6H). ESMS calculated forC₂₄H₂₈N₂O₄ was 408.2; ESMS found was 409.4 (M+H)⁺.

Compounds 2 and 4 were synthesized using techniques analogous to thosefor Compound 1. Additionally, compounds 35-49 can be synthesized usingthis method.

Example 2 Synthesis of Compound 3

Step-1:

To a stirred solution of 0.33 g (1.51 mmols) of 1 and 0.50 g (3.02mmols) of the boronic acid 2 in 15 mL of anhydrous dichloromethane wasadded 0.41 g (2.27 mmols) of Cu(OAc)₂ followed by 0.25 mL (3.02 mmols)of pyridine at 0° C. The mixture was warmed up to room temperature andstirred over the weekend. Water workup and chromatography on silica gelafforded 0.11 g of the product 3 as colorless liquid.

Step-2:

To a suspension of 0.12 g (0.32 mmols) of the boronic acid 4 and 0.11 g(0.32 mmols) of product 3 from previous step, was added 0.27 g (0.81mmols) of Cs₂CO₃ in 8 mL of dioxane and 2 mL of water and was stirredunder argon atmosphere at room temperature. To the resultant mixture wasadded 5 mg of Pd₂(dba)₃ (8 μmols) followed by 10 mg oftriphenylphosphine (32 μmols) and the flask was thoroughly flushed withargon. The flask was then heated at 100° C. overnight and concentrated.Water workup followed by concentration of the organics and columnchromatography afforded 0.10 g of the product 5 as white solid.

Step 3:

0.10 g of product 5 from STEP-2 was dissolved in 15 mL of 1:1:1THF:MeOH:H₂O and was refluxed with 5 mL of 2N NaOH overnight. Theresultant mixture was concentrated to remove the organics andneutralized with 2N HCl to pH equaled to 5. The acid product was thenextracted with ethyl acetate, dried over anhydrous sodium sulfate andconcentrated to give 70 mg of the product.

Step-4:

To the product obtained in step 3 (70 mg, 0.125 mmols) was added, 0.13mL (0.25 mmols, 2.0N in THF) of ethylamine, 30 mg (0.15 mmols) ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 3 mg of4-dimethylaminopyridine in 10 mL of dichloromethane and stirred for 2 h.Water workup followed by concentration afforded 60 m of the amideproduct 6.

Step 5:

The above-mentioned amide 6 was hydrogenated using Pd—C (10% wet-type)to afford 15 mg of the product.

¹H-NMR (CDCl₃, 300 MHz): δ 6.99 (d, J=3.0 Hz, 1H), 6.98 (d, J=6.9 Hz,2H), 6.57 (d, J=6.9 Hz, 2H), 6.51 (s, 1H), 6.34 (d, J=3.0 Hz), 6.22 (s,1H), 5.98 (bs, 1H), 5.71 (bs, 1H), 5.47 (t, J=4.2 Hz, 1H), 3.25(quintet, 4.2 Hz, 2H), 2.96 (septet, J=5.1 Hz, 1H), 2.89 (s, 6H), 0.96(t, J=4.8 Hz, 3H), 0.93 (d, J=5.1 Hz, 6H). ESMS calculated forC₂₄H₂₉N₃O₃ was 407.22; ESMS found was 408.2 (M+H)⁺.

Additionally, propethic compounds 5-34 can be synthesized using thismethod.

Example 3 Inhibition of Hsp90

Hsp90 protein is obtained from Stressgen (Cat# SPP-770). Assay buffer:100 mM Tris-HCl, Ph 7.4, 20 mM KCl, 6 mM MgCl₂. Malachite green (0.0812%w/v) (M9636) and polyvinyl alcohol USP (2.32% w/v) (P1097) are obtainedfrom Sigma. A Malachite Green Assay (see Methods Mol. Med., 85:149(2003) for method details) is used for examination of ATPase activity ofHsp90 protein. Briefly, Hsp90 protein in assay buffer (100 mM Tris-HCl,Ph 7.4, 20 mM KCl, 6 mM MgCl₂) is mixed with ATP alone (negativecontrol) or in the presence of Geldanamycin (a positive control) or acompound of the invention in a 96-well plate. Malachite green reagent isadded to the reaction. The mixtures are incubated at 37° C. for 4 hoursand sodium citrate buffer (34% w/v sodium citrate) is added to thereaction. The plate is read by an ELISA reader with an absorbance at 620nm.

Example 4 Degradation of Hsp90 Client Proteins Via Inhibition of Hsp90Activity

A. Cells and Cell Culture

Human high-Her2 breast carcinoma BT474 (HTB-20), SK-BR-3 (HTB-30) andMCF-7 breast carcinoma (HTB-22) from American Type Culture Collection,VA, USA were grown in Dulbecco's modified Eagle's medium with 4 mML-glutamine and antibiotics (100 IU/ml penicillin and 100 μg/mlstreptomycine; GibcoBRL). To obtain exponential cell growth, cells weretrypsinized, counted and seeded at a cell density of 0.5×10⁶ cells/mlregularly, every 3 days. All experiments were performed on day 1 aftercell passage.

B. Degradation of Her2 in Cells after Treatment with a Compound of theInvention

1. Method 1

BT-474 cells are treated with 0.5 μM, 2 μM, or 5 μM of 17AAG (a positivecontrol) or 0.5 μM, 2 μM, or 5 μM of a compound of the inventionovernight in DMEM medium. After treatment, each cytoplasmic sample, isprepared from 1×10⁶ cells by incubation of cell lysis buffer (#9803,Cell Signaling Technology) on ice for 10 minutes. The resultingsupernatant used as the cytosol fractions is dissolved with samplebuffer for SDS-PAGE and run on a SDS-PAGE gel, blotted onto anitrocellulose membrane by using semi-dry transfer. Non-specific bindingto nitrocellulose is blocked with 5% skim milk in TBS with 0.5% Tween atroom temperature for 1 hour, then probed with anti-Her2/ErB2 mAb (rabbitIgG, #2242, Cell Signaling) and anti-Tubulin (T9026, Sigma) ashousekeeping control protein. HRP-conjugated goat anti-rabbit IgG (H+L)and HRP-conjugated horse anti-mouse IgG (H+L) are used as secondary Ab(#7074, #7076, Cell Signaling) and LumiGLO reagent, 20× Peroxide (#7003,Cell Signaling) is used for visualization.

Her2, an Hsp90 client protein, is expected to be degraded when cells aretreated with compounds of the invention. 0.5 μM of 17AAG, a known Hsp90inhibitor which is used as a positive control, causes partialdegradation of Her2.

2. Method 2

MV-4-11 cells (20,000 cells/well) were cultured in 96-well plates andmaintained at 37° C. for several hours. The cells were treated with acompound of the invention or 17AAG (a positive control) at variousconcentrations and incubated at 37° C. for 72 hours. Cell survival wasmeasured with Cell Counting Kit-8 (Dojindo Laboratories, Cat. # CK04).

The IC₅₀ range for Her2 degradation by compounds of the invention arelisted below in Table 2.

TABLE 2 IC₅₀ range of compounds of the invention for inhibition of Hsp90Compound IC₅₀ (nM) Number ≦20  none 20< × ≦50  none 50< × <100 none 100<× <500  1 500< × <1000 2, 4 >1000 3

C. Fluorescent Staining of Her2 on the Surface of Cells Treated with aCompound of the Invention

After treatment with a compound of the invention, cells are washed twicewith 1×PBS/1% FBS, and then stained with anti-Her2-FITC (#340553, BD)for 30 min at 4° C. Cells are then washed three times in FACS bufferbefore the fixation in 0.5 ml 1% paraformadehydrede. Data is acquired ona FACSCalibur system. Isotype-matched controls are used to establish thenon-specific staining of samples and to set the fluorescent markers. Atotal 10,000 events are recorded from each sample. Data are analyzed byusing CellQuest software (BD Biosciences).

D. Apoptosis Analysis

After treatment with the compounds of the invention, cells are washedonce with 1×PBS/1% FBS, and then stained in binding buffer withFITC-conjugated Annexin V and Propidium iodide (PI) (all obtained fromBD Biosciences) for 30 min at 4° C. Flow cytometric analysis isperformed with FACSCalibur (BD Biosciences) and a total 10,000 eventsare recorded from each sample. Data is analyzed by using CellQuestsoftware (BD Biosciences). The relative fluorescence is calculated aftersubtraction of the fluorescence of control.

E. Degradation of c-Kit in Cells after Treatment with a Compound of theInvention

Two leukemia cell lines, HEL92.1.7 and Kasumi-1, are used for testingc-Kit degradation induced by Hsp90 inhibitors of the invention. Thecells (3×10⁵ per well) are treated with 17AAG (0.5 μM), or a compound ofthe invention for about 18 h. The cells are collected and centrifuged(SORVALL RT 6000D) at 1200 rpm for 5 min. The supernatants arediscarded, and the cells are washed one time with 1×PBS. Aftercentrifugation the cells are stained with FITC conjugated c-Kit antibody(MBL International, Cat# K0105-4) in 100 ml 1×PBS at 4° C. for 1 h. Thesamples are read and analyzed with FACSCalibur flow cytometer (BectonDicknson).

c-Kit, a tyrosine kinase receptor and one of the Hsp90 client proteins,is selected and used in a FACS-based degradation assay. Compounds of theinvention are expected to induce c-Kit degradation in a dose-dependentmanner. Compounds of the invention are expected to be effective in thetreatment of c-Kit associated tumors, such as leukemias, mast celltumors, small cell lung cancer, testicular cancer, some cancers of thegastrointestinal tract (including GIST), and some central nervoussystem.

The results of the FACS analysis can be confirmed with Western blotanalysis.

F. Degradation of c-Met in Cells after Treatment with a Compound of theInvention

The ability of the Hsp90 inhibitors of the invention to induce thedegradation of c-Met, an Hsp90 client protein that is expressed at highlevels in several types of non-small cell lung cancer can be examined.NCI-H1993 (ATCC, cat# CRL-5909) are seeded in 6-well plates at 5×10⁵cells/well. The cells are treated with 17AAG (100 nM or 400 nM) or acompound of the invention (100 nM or 400 nM), and cell lysis is prepared24 h after treatment. Equal amount of proteins are used for Western blotanalysis. The compounds of the invention are expected to potently inducedegradation of c-Met in this cell line due to inhibition of Hsp90.

Example 5 Anti-Tumor Activity Against the Human Tumor Cell LineMDA-MB-435S in a Nude Mouse Xenograft Model

The human tumor cell line, MDA-MB-435S (ATCC #HTB-129; G. Ellison, etal., Mol. Pathol. 55:294-299, 2002), is obtained from the American TypeCulture Collection (Manassas, Va., USA). The cell line is cultured ingrowth media prepared from 50% Dulbecco's Modified Eagle Medium (highglucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1% 100×L-glutamine, 1% 100× Penicillin-Streptomycin, 1% 100× sodium pyruvateand 1% 100×MEM non-essential amino acids. FBS is obtained fromSigma-Aldrich Corp. (St. Louis, Mo., USA), and all other reagents areobtained from Invitrogen Corp. (Carlsbad, Calif., USA). Approximately4-5×10⁶ cells that have been cryopreserved in liquid nitrogen arerapidly thawed at 37° C. and transferred to a 175 cm² tissue cultureflask containing 50 ml of growth media and then incubated at 37° C. in a5% CO₂ incubator. The growth media is replaced every 2-3 days until theflask becomes 90% confluent, typically in 5-7 days. To passage andexpand the cell line, a 90% confluent flask is washed with 10 ml of roomtemperature phosphate buffered saline (PBS) and the cells aredisassociated by adding 5 ml 1× Trypsin-EDTA (Invitrogen) and incubatingat 37° C. until the cells detach from the surface of the flask. Toinactivate the trypsin, 5 ml of growth media is added and then thecontents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 ml ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10⁶ cells per flask are seeded into 175 cm² flaskscontaining 50 ml of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells have been obtained forimplantation into mice.

Six to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 7 and 12 weeksof age at implantation. To implant tumor cells into nude mice, the cellsare trypsinized as above, washed in PBS and resusupended at aconcentration of 50×10⁶ cells/ml in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 ml of the cell suspension is injected into the corpusadiposum of nude mice. The corpus adiposum is a fat body located in theventral abdominal vicera in the right quadrant of the abdomen at thejuncture of the os coxae (pelvic bone) and the os femoris (femur).Tumors are then permitted to develop in vivo until they reachapproximately 150 mm³ in volume, which typically requires 2-3 weeksfollowing implantation. Tumor volumes (V) are calculated by calipermeasurement of the width (W), length (L) and thickness (T) of tumorsusing the following formula: V=0.5326×(L×W×T). Animals are randomizedinto treatment groups so that the average tumor volumes of each groupare similar at the start of dosing.

Stock solutions of test compounds are prepared by dissolving theappropriate amounts of each compound in dimethyl sulfoxide (DMSO) bysonication in an ultrasonic water bath. Stock solutions are prepared atthe start of the study, stored at −20° C. and diluted fresh each day fordosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenatedcastor oil (BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany)) in80% D5W (5% dextrose in water (Abbott Laboratories, North Chicago, Ill.,USA)) is also prepared by first heating 100% Cremophore RH40 at 50-60°C. until liquefied and clear, diluting 1:5 with 100% D5W, reheatingagain until clear and then mixing well. This solution is stored at roomtemperature for up to 3 months prior to use. To prepare formulations fordaily dosing, DMSO stock solutions are diluted 1:10 with 20% CremophoreRH40. The final formulation for dosing contains 10% DMSO, 18% CremophoreRH40, 3.6% dextrose and 68.4% water and the appropriate amount of testarticle. Animals are intraperitoneal (IP) injected with this solution at10 ml per kg body weight on a schedule of 5 days per week (Monday thruFriday, with no dosing on Saturday and Sunday) for 3 weeks.

Compounds of the invention are expected to result in decreased thegrowth rate of MDA-MB-435S cells in nude mice to a greater extent than adose of 100 mg/kg body weight of the Hsp90 inhibitor 17-AAG.

Example 6 Anti-Tumor Activity Against Human

Tumor Cells in a Nude Mouse Xenograft Model

The human squamous non-small cell lung cancer cell line, RERF-LC-AI(RCB0444; S. Kyoizumi, et al., Cancer. Res. 45:3274-3281, 1985), isobtained from the Riken Cell Bank (Tsukuba, Ibaraki, Japan). The cellline is cultured in growth media prepared from 50% Dulbecco's ModifiedEagle Medium (high glucose), 50% RPMI Media 1640, 10% fetal bovine serum(FBS), 1% 100× L-glutamine, 1% 100× penicillin-streptomycin, 1% 100×sodium pyruvate and 1% 100×MEM non-essential amino acids. FBS isobtained from American Type Culture Collection (Manassas, Va., USA) andall other reagents are obtained from Invitrogen Corp. (Carlsbad, Calif.,USA). Approximately 4-5×10⁶ cells that have been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 ml of growth media and then incubatedat 37° C. in a 5% CO₂ incubator.

The growth media is replaced every 2-3 days until the flask becomes 90%confluent, typically in 5-7 days. To passage and expand the cell line, a90% confluent flask is washed with 10 ml of room temperature phosphatebuffered saline (PBS) and the cells are disassociated by adding 5 ml 1×trypsin-EDTA (Invitrogen) and incubating at 37° C. until the cellsdetach from the surface of the flask. To inactivate the trypsin, 5 ml ofgrowth media is added and then the contents of the flask are centrifugedto pellet the cells. The supernatant is aspirated and the cell pellet isresuspended in 10 ml of growth media and the cell number determinedusing a hemocytometer. Approximately 1-3×10(6) cells per flask areseeded into 175 cm² flasks containing 50 ml of growth media andincubated at 37° C. in a 5% CO₂ incubator. When the flasks reach 90%confluence, the above passaging process is repeated until sufficientcells have been obtained for implantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 8 and 12 weeksof age at implantation. To implant RERF-LC-AI tumor cells into nudemice, the cells are trypsinized as above, washed in PBS and resuspendedat a concentration of 50×10⁶ cells/ml in 50% non-supplemented RPMI Media1640 and 50% Matrigel Basement Membrane Matrix (#354234; BD Biosciences;Bedford, Mass., USA). Using a 27 gauge needle and 1 cc syringe, 0.1 mlof the cell suspension is injected subcutaneously into the flank of eachnude mouse. Tumor volumes (V) are calculated by caliper measurement ofthe width (W), length (L) and thickness (T) of tumors using thefollowing formula: V=0.5236×(L×W×T).

In vivo passaged RERF-LC-AI tumor cells (RERF-LC-AI^(IVP)) are isolatedto improve the rate of tumor implantation relative to the parental cellline in nude mice. RERF-LC-AI tumors are permitted to develop in vivountil they reach approximately 250 mm³ in volume, which requiresapproximately 3 weeks following implantation. Mice are euthanized viaCO₂ asphyxiation and their exteriors sterilized with 70% ethanol in alaminar flow hood. Using sterile technique, tumors are excised and dicedin 50 ml PBS using a scalpel blade. A single cell suspension is preparedusing a 55 ml Wheaton Safe-Grind tissue grinder (catalog #62400-358; VWRInternational, West Chester, Pa., USA) by plunging the pestle up anddown 4-5 times without twisting. The suspension is strained through a 70μM nylon cell strainer and then centrifuged to pellet the cells. Theresulting pellet is resuspended in 0.1 M NH₄Cl to lyse contaminating redblood cells and then immediately centrifuged to pellet the cells. Thecell pellet is resuspended in growth media and seeded into 175 cm²flasks containing 50 ml of growth media at 1-3 tumors/flask orapproximately 10×10⁶ cells/flask. After overnight incubation at 37° C.in a 5% CO₂ incubator, non-adherent cells are removed by rinsing twotimes with PBS and then the cultures are fed with fresh growth media.When the flasks reach 90% confluence, the above passaging process isrepeated until sufficient cells have been obtained for implantation intomice.

RERF-LC-AI^(IVP) cells are then implanted as above and tumors arepermitted to develop in vivo until the majority reached an average of100-200 mm³ in tumor volume, which typically requires 2-3 weeksfollowing implantation. Animals with oblong or very small or largetumors are discarded, and only animals carrying tumors that displayconsistent growth rates are selected for studies. Animals are randomizedinto treatment groups so that the average tumor volumes of each groupare similar at the start of dosing.

The HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG),can be employed as a positive control (Albany Molecular Research,Albany, N.Y., USA). Stock solutions of test articles are prepared bydissolving the appropriate amounts of each compound in dimethylsulfoxide (DMSO) by sonication in an ultrasonic water bath. Stocksolutions are prepared weekly, stored at −20° C. and diluted fresh eachday for dosing. A solution of 20% Cremophore RH40 (polyoxyl 40hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen,Germany) in 80% D5W (5% dextrose in water; Abbott Laboratories, NorthChicago, Ill., USA) is also prepared by first heating 100% CremophoreRH40 at 50-60° C. until liquefied and clear, diluting 1:5 with 100% D5W,reheating again until clear and then mixing well. This solution isstored at room temperature for up to 3 months prior to use. To prepareformulations for daily dosing, DMSO stock solutions are diluted 1:10with 20% Cremophore RH40. The final formulation for dosing contains 10%DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and theappropriate amount of test article. Animals are intraperitoneally (i.p.)injected with this solution at 10 ml per kg body weight on a schedule of5 days per week (Monday, Tuesday, Wednesday, Thursday and Friday, withno dosing on Saturday and Sunday) for a total of 15 doses.

Treatment with compounds of the invention is expected to result in thedecreased growth rate of RERF-LC-AI^(IVP) human lung tumor cells in nudemice.

Example 7 Necrosis in a Nude Mouse Tumor Model

The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), isobtained from the American Type Culture Collection (ATCC; Manassas, Va.,USA). The cell line is cultured in growth media prepared from 50%Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640,10% fetal bovine serum (FBS), 1% 100× L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100×MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10⁶ cells that have been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 ml of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media is replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask is washed with10 ml of room temperature phosphate buffered saline (PBS) and the cellsare disassociated by adding 5 ml 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detach from the surface of theflask. To inactivate the trypsin, 5 ml of growth media is added and thenthe contents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 ml ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10⁶ cells per flask are seeded into 175 cm² flaskscontaining 50 ml of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells have been obtained forimplantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 8 and 10 weeksof age at implantation. To implant EMT6 tumor cells into nude mice, thecells are trypsinized as above, washed in PBS and resusupended at aconcentration of 10×10⁶ cells/ml in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 ml of the cell suspension is injected subcutaneouslyinto the flank of each nude mouse.

Tumors are then permitted to develop in vivo until the majority reached75-125 mm³ in tumor volume, which typically requires 1 week followingimplantation. Animals with oblong, very small or large tumors arediscarded, and only animals carrying tumors that display consistentgrowth rates are selected for studies. Tumor volumes (V) are calculatedby caliper measurement of the width (W), length (L) and thickness (T) oftumors using the following formula: V=0.5236×(L×W×T). Animals arerandomized into treatment groups so that each group had median tumorvolumes of approximately 100 mm³ at the start of dosing.

To formulate a compound of the invention in DRD, a stock solution of thetest article is prepared by dissolving an appropriate amount of thecompound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonicwater bath. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenatedcastor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 5%dextrose in water (Abbott Laboratories, North Chicago, Ill., USA) isalso prepared by first heating 100% Cremophore RH40 at 50-60° C. untilliquefied and clear, diluting 1:5 with 100% D5W, reheating again untilclear and then mixing well. This solution is stored at room temperaturefor up to 3 months prior to use. To prepare a DRD formulation fordosing, the DMSO stock solution is diluted 1:10 with 20% CremophoreRH40. The final DRD formulation for dosing contains 10% DMSO, 18%Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amountof test article.

Tumor-bearing animals are given a single intravenous (i.v.) bolusinjections of either DRD vehicle or a compound of the inventionformulated in DRD, both at 10 mL per kg body weight. Then, 4-24 hr afterdrug treatment, tumors are excised, cut in half and fixed overnight in10% neutral-buffered formalin. Each tumor is embedded in paraffin withthe cut surfaces placed downwards in the block, and rough cut until acomplete section is obtained. From each tumor, 5 μM serial sections areprepared and stained with hematoxylin and eosin. Slides are evaluatedmanually using light microscopy with a 10×10 square gridded reticle. Thepercentage of necrosis in a tumor is quantified at 200× magnification byscoring the total number of grid squares containing necrosis and thetotal number of grid squares containing viable tumor cells.

It is expected that compounds of the invention will result in anincrease in necrotic tissue in the center of EMT6 tumors relative to thebaseline necrosis observed in vehicle treated tumors. As would beexpected for a vascular targeting mechanism of action, rapid onset ofnecrosis is consistent with there being a loss of blood flow to tumorsresulting in hypoxia and tumor cell death.

Example 8 Vascular Disrupting Activities in a Nude Mouse Tumor Model

The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), isobtained from the American Type Culture Collection (ATCC; Manassas, Va.,USA). The cell line is cultured in growth media prepared from 50%Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640,10% fetal bovine serum (FBS), 1% 100× L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100×MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10⁶ cells that have been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 mL of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media is replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask is washed with10 mL of room temperature phosphate buffered saline (PBS) and the cellsare disassociated by adding 5 mL 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detach from the surface of theflask. To inactivate the trypsin, 5 mL of growth media is added and thenthe contents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 mL ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10⁶ cells per flask are seeded into 175 cm² flaskscontaining 50 mL of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells have been obtained forimplantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 8 and 10 weeksof age at implantation. To implant EMT6 tumor cells into nude mice, thecells are trypsinized as above, washed in PBS and resusupended at aconcentration of 10×10⁶ cells/mL in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 mL of the cell suspension is injected subcutaneouslyinto the flank of each nude mouse.

For the Evans Blue dye assay, tumors are permitted to develop in vivountil the majority reach 40-90 mm³ in tumor volume (to minimize theextent of tumor necrosis), which typically require 4-6 days followingimplantation. Animals with visibly necrotic, oblong, very small or verylarge tumors are discarded and only animals carrying tumors that displayconsistent growth rates are selected for use. Tumor volumes (V) arecalculated by caliper measurement of the width (W), length (L) andthickness (T) of tumors using the following formula: V=0.5236×(L×W×T).Animals are randomized into treatment groups so that at the start ofdosing each group have median tumor volumes of approximately 125 mm³ orapproximately 55 mm³ for the Evans Blue dye assay.

To formulate compounds of the invention for dosing, the appropriateamount of compound is dissolved in 5% dextrose in water (D5W; AbbottLaboratories, North Chicago, Ill., USA). Vehicle-treated animals aredosed with D5W.

To conduct the Evans Blue dye assay, tumor-bearing animals are dosedwith vehicle or test article at 0 hr, and then i.v. injected with 100μL, of a 1% (w/v) Evan's Blue dye (Sigma #E-2129; St. Louis, Mo., USA)solution in 0.9% NaCl at +1 hr. Tumors are excised at +4 hr, weighed andthe tissue disassociated by incubation in 50 μL 1 N KOH at 60° C. for 16hr. To extract the dye, 125 μL of a 0.6 N phosphoric acid and 325 μLacetone are added, and the samples vigorously vortexed and thenmicrocentrifuged at 3000 RPM for 15 min to pellet cell debris. Theoptical absorbance of 200 μL of supernatant is then measured at 620 nMin a Triad spectrophotometer (Dynex Technologies, Chantilly, Va., USA).

Background OD₆₂₀ values from similarly sized groups of vehicle or testarticle-treated animals that have not been injected with dye aresubtracted as background. OD₆₂₀ values are then normalized for tumorweight and dye uptake is calculated relative to vehicle-treated tumors.

To examine the vascular disrupting activity of a compound of theinvention, the Evans Blue dye assay is employed as a measurement oftumor blood volume. Graff et al., Eur. J. Cancer 36:1433-1440 (2000).Evans Blue dye makes a complex with serum albumin by electrostaticinteraction between the sulphonic acid group of the dye and the terminalcationic nitrogens of the lysine residues in albumin. The dye leaves thecirculation very slowly, principally by diffusion into extravasculartissues while still bound to albumin. Albumin-dye complex taken up bytumors is located in the extracellular space of non-necrotic tissue, andintracellular uptake and uptake in necrotic regions is negligible. Theamount of dye present in a tumor is a measurement of the tumor bloodvolume and microvessel permeability. Compounds of the invention areexpected to result in substantially decreased tumor dye uptake relativeto vehicle-treated animals. Such a decrease in dye penetration into thetumor is consistent with there being a loss of blood flow to tumors dueto blockage of tumor vasculature, consistent with a vascular disruptingmechanism of action.

Example 9 Inhibition of the Production of Inflammatory Cytokines inHuman PBMCs

Human PBMC are isolated using Ficoll 400 and diatrizoate sodium (density1.077 g/ml) solution and purified with RosetteSep (StemCellTechnologies). The PBMCs are primed with human IFN-γ (800 U/ml, PierceBiotechnology #R-IFNG-50), seeded at 0.5×10⁶/100 μL/well in 96-wellU-bottom plate with culture medium (RPMI 1640, 10% FBS, 1% Pen/Strep),and incubated in 37° C. for overnight. The cells are then stimulatedwith 1 μg/ml of LPS (Lipopolysaccharide, Sigma#L2654-1MG) or 0.025% ofSAC (Staphylococcus Aureus Cowan, Calbiochem-Novabiochem Corp. #507858),and treated with a test compound at different concentrations with finalDMSO concentration less than 0.5% for 16-18 hrs. About 180 μl/well ofsupernatant is collected and measured using ELISA kit or Bio-plex(Bio-Rad) to determine the levels of cytokine production. The cellsurvival is determined using Cell Counting Kit-8 (Dojindo MolecularTechnologies, Inc.). Compounds of the invention are expected to broadlyinhibit the production of proinflammatory cytokines.

Example 10 Suppression of Glucocorticoid Receptor Levels in Rat andHuman PBMCs

Cell Preparation:

Whole blood samples from healthy human volunteers and male SD rats arecollected and the PBMCs are isolated immediately as follows. 5 ml ofwhole blood is diluted with an equal volume of sterile 1×PBS. Thediluted blood is overlayed carefully into a sterile centrifuge tubewithout disturbing the bottom layer that containing 5 ml of Ficoll-paqueplus density gradient solution. The layered blood is centrifuged at1500×g for 30 minutes at room temperature. The middle thin layercontaining PBMCs is carefully removed, transferred to another sterilecentrifuge tube, and washed twice with PBS to remove Percoll. Isolatedrat and human PBMCs are cultured in 10% fetal bovine serum/DMEM.

Treatment:

The rat and human PBMCs are treated with DMSO (control), compounds ofthe invention, or 17-DMAG at concentrations of 0, 1, 5, 25, or 100 nM(in DMSO) for 16 hours. The cells are then collected and rinsed inice-cold PBS and stored in liquid nitrogen until further analysis.

Immunoblot

PBMC are prepared in Western lysis buffer (10 mmol/L HEPES, 42 mmol/LKCl, 5 mmol/L MgCl₂, 0.1 mmol/L EDTA, 0.1 mmol/L EGTA, 1 mmol/L DTT, 1%Triton X-100, freshly supplemented with 1× protease inhibitor cocktailfrom Pierce, Rockford, Ill.). Lysate protein concentrations arequantified by bicinchoninic acid assay (Pierce) and normalized. Equalamounts of protein are loaded onto 10% NuPAGE Bis-Tris Gels (Invitrogen)and subsequently transferred onto polyvinylidene difluoride membranes.The membranes are blocked in 5% milk in TBST. Primary antibody ofglucocorticod receptor from Santa Cruz Biotechnology, Inc. is added andincubated at room temperature for 1 hour with shaking. The blots arewashed extensively in TBST before secondary antibodies are added forovernight incubation at 4° C. with gentle shaking. The blots are againwashed extensively and developed with SuperSignal West Femto substrate(Pierce). The immunoblot analysis is performed to measure the level oftotal GRs by Quantity One software from Bio-Rad.

Example 11 Suppression of Glucocorticoid Receptor Levels in Human PBMCsand Renal Cells, as Well as in Several Human Cancer Cell Lines

Cell Preparation:

Normal human renal proximal tubule epithelial cells and tumor cell linesof MV-4-11, Kasumi-1, and Hela are obtained from Cambrex Bioproducts andAmerican Type Culture Collection, respectively. Cells are cultured with10% fetal bovine serum/DMEM.

The whole blood samples from healthy human volunteers are collected andthe PBMCs are isolated immediately as described in Example 10. Isolatedhuman PBMCs are cultured in 10% fetal bovine serum/DMEM.

Treatment:

Human PBMCs, kasumi-1, My-4-11, Hela, and human renal proximal tubuleepithelial cells are treated with DMSO (control), compounds of theinvention, 17-DMAG at concentrations of 0, 5, 25, or 100 nM (in DMSO)for 16 hours. The cells are then collected and rinsed in ice-cold PBSand stored in liquid nitrogen until further analysis.

Immunoblot

PBMC, renal and tumor cell pellets are prepared in Western lysis buffer(10 mmol/L HEPES, 42 mmol/L KCl, 5 mmol/L MgCl₂, 0.1 mmol/L EDTA, 0.1mmol/L EGTA, 1 mmol/L DTT, 1% Triton X-100, freshly supplemented with 1×protease inhibitor cocktail from Pierce, Rockford, Ill.). Lysate proteinconcentrations are quantified by bicinchoninic acid assay (Pierce) andnormalized. Equal amounts of protein are loaded onto 10% NuPAGE Bis-TrisGels (Invitrogen) and subsequently transferred onto polyvinylidenedifluoride membranes. The membranes are blocked in 5% milk in TBST.Primary antibody of glucocorticod receptor from Santa CruzBiotechnology, Inc. is added and incubated at room temperature for 1hour with shaking. The blots are washed extensively in TBST beforesecondary antibodies are added for overnight incubation at 4° C. withgentle shaking. The blots are again washed extensively and developedwith SuperSignal West Femto substrate (Pierce). Compounds of theinvention are expected to suppress the expression of glucocorticoidreceptors in cancer cells as well as in normal PBMCs and renal cells.

Example 12 Suppression of Glucocorticoid Receptor Levels In Vivo

Male adult Sprague-Dawley (SD) rats, five per group, are randomlyassigned into five testing groups which received treatments as shown inTable 3:

TABLE 3 Treatment group Treatment received G1  5 mL/kg of vehicle (5%DMSO/13.5% Cr-RH40/D5W) G2  6 mg/kg of 17-DMAG G3  5 mg/kg of PaclitaxelG4 80 mg/kg of Compound of the invention G5 50 mg/kg of Compound of theinvention

The test compounds are administered daily intravenously via tail veinfor four days. All rats are sacrificed at the study day 5. About 1-2 mLof blood samples are collected per animal. The blood samples are thenpulled together as a group for PBMC isolation. PBMCs are isolated and animmunoblot using an antibody that recognizes the glucocorticoid receptoris prepared, as described in Examples 10 and 11.

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

The invention claimed is:
 1. A method of treating a proliferativedisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound represented by the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein: each R¹ and R²is independently —NR¹⁰R¹¹, —OR⁷, or —SR⁷; R³ is hydrogen, —X⁵⁰R⁵⁰,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl,aralkyl, and heteraralkyl represented by R³ is optionally andindependently substituted; each R⁴ and R⁵ is independently hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl,aralkyl, and heteraralkyl represented by R⁴ or R⁵ is optionally andindependently substituted; each R⁷ is independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl,aralkyl, and heteraralkyl represented by R⁷ is optionally andindependently substituted; each R¹⁰ and R¹¹ is independently hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl,aralkyl, and heteraralkyl represented by R¹⁰ or R¹¹ is optionally andindependently substituted; or R¹⁰ and R¹¹, taken together with thenitrogen to which they are attached, form an optionally substitutedheterocyclyl or an optionally substituted heteroaryl; R⁵⁰ is anoptionally substituted aryl or an optionally substituted heteroaryl; X⁵⁰is a divalent group selected from a C₁-C₄ alkylene, NR⁷, C(O), C(S),C(NR⁷), and S(O)_(p); Y is O or S; each Z is independently alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, halo, cyano,nitro, guanadino, or alkoxy, wherein the alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl,heteroaralkyl represented by Z are optionally and independentlysubstituted; each optional substituent for an alkyl, alkylene, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl,heteroaryl, and heteroaralkyl is independently an alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl,aralkyl, heteraralkyl, heteroalkyl, alkoxy, halo, cyano, nitro, orguanadino; each p is independently 0, 1 or 2; and n is 0, 1, 2, or
 3. 2.The method of claim 1, wherein the proliferative disorder is a cancer.3. The method of claim 2, wherein the cancer is a c-Kit associatedcancer.
 4. The method of claim 2, wherein the cancer is a BCR-ABLassociated cancer.
 5. The method of claim 2, wherein the cancer is aFLT3 associated cancer.
 6. The method of claim 2, wherein the cancer isan EGFR associated cancer.
 7. The method of claim 1, wherein the subjectis human.
 8. The method of claim 2, wherein the cancer is anon-Hodgkin's lymphoma.
 9. The method of claim 8, wherein thenon-Hodgkin's lymphoma is a B-cell non-Hodgkin's lymphoma.
 10. Themethod of claim 9, wherein the B-cell non-Hodgkin's lymphoma is selectedfrom the group consisting of Burkitt's lymphoma, follicular lymphoma,diffuse large B-cell lymphoma, nodal marginal zone B-cell lymphoma,plasma cell neoplasms, small lymphocytic lymphoma/chronic lymphocyticleukemia, mantle cell lymphoma, and lymphoplamacyticlymphoma/Waldenstrom macroglobulinemia.
 11. The method of claim 8,wherein the non-Hodgkin's lymphoma is a T-cell non-Hodgkin's lymphoma.12. The method of claim 11, wherein the T-cell non-Hodgkin's lymphoma isselected from the group consisting of anaplastic large-cell lymphoma,precursor-T-cell lymphoblastic leukemia/lymphoma, unspecified peripheralT-cell lymphoma, and angioimmunoblastic T-cell lymphoma.
 13. The methodof claim 1, wherein the proliferative disorder is an inflammatorydisorder.
 14. The method of claim 13, wherein the inflammatory disorderis selected from the group consisting of a transplant rejection, achronic inflammatory disorder of the joints, an inflammatory boweldisease, an inflammatory lung disorder, an inflammatory disorder of theeye, a chronic inflammatory disorder of the gums, an inflammatorydisease of the kidney, an inflammatory disorder of the skin, aninflammatory disease of the central nervous system, an inflammatorydisease of the heart, and a systemic inflammation.